Cette partie de l’équipe a pour thématique la conception de sondes novatrices pour l’imagerie médicale, ainsi que l’imagerie par Résonance Magnétique (IRM) du petit animal.
A. Conception de sondes d’imagerie
Notre chimie est axée sur le design, la synthèse et la caractérisation de sondes innovantes, basée sur des complexes métalliques et principalement des complexes de lanthanides, pour des applications en IRM. Nous mettons en œuvre les principes de la chimie de coordination afin de concevoir des sondes d’imagerie moléculaire. De plus, nous nous intéressons aussi à des aspects fondamentaux comme l’optimisation de la stabilité des complexes et la compréhension des phénomènes qui régissent l’efficacité des systèmes paramagnétiques en IRM. Nous travaillons ainsi sur plusieurs étapes du développement des sondes d’imagerie : (i) la conception et la synthèse de nouveaux chélatants, (ii) la caractérisation physico-chimique complète des complexes métalliques, ce qui comprend la détermination des paramètres microscopiques individuels qui gouvernent la relaxivité ou le transfert de saturation par échange chimique (CEST), (iii) l’estimation de la stabilité et de l’inertie cinétique des complexes, essentielles par rapport à la toxicité in vivo, (iv) l’évaluation IRM in vitro/in vivo des agents de contraste.
Principaux projets en cours :
Agents IRM sensibles aux enzymes :
Nous travaillons sur des sondes IRM présentant un espaceur auto-immolable entre le complexe de Ln3+et le substrat spécifique de l’enzyme cible. La coupure enzymatique provoque une cascade électronique, ce qui entraine une modification structurale du complexe et, de ce fait, une réponse simultanée en relaxivité ou en PARACEST. Cette plateforme enzymatique a pu être étendue à la détection optique en introduisant un chromophore (pyridine) au ligand. Ceci constitue le premier exemple où une même molécule peut être utilisée comme agent répondant aux enzymes dans trois modalités d’imagerie différentes et indépendantes (IRM par pondération T1 et par transfert de saturation par échange chimique, imagerie optique). Ces résultats ont été récemment publiés (J. Am. Chem. Soc. 2016, 138, 2913−2916) and highlighted on the cover of JACS (collab. P. Durand, ICSN, and S. Petoud).
Détection des neurotransmetteurs (NT) :
Ceci a été réalisé en synthétisant une plateforme moléculaire qui possède deux parties distinctes de reconnaissance pour les neurotransmetteurs zwittérioniques. La reconnaissance des NTs se présente via des interactions ditopiques (i) entre un chélate de Gd3+ chargé positivement et la fonction carboxylate du neurotransmetteur, et (ii) entre un éther-couronne triazoté et la fonction amine du neurotransmetteur (figure). Une sonde a été utilisée avec succès pour suivre l’activité neuronale dans de fines tranches de cerveau de souris. Ceci a montré, pour la première fois que des sondes à base de Gd3+ pouvaient être une alternative pour le suivi de l’activité du cerveau dans des conditions biologiques pertinentes (collab. G. Angelovski, Max Planck Tübingen, ACS Chem. Neuroscience, 2015, 6, 219-225 ; Chem. Eur. J. 2015, 21, 11226-11237).
Détection de Zn2+ : Des complexes de Gd3+ sont conçus suivant un système modulaire couplant, via différents espaceurs, un dérivé de pyridine pour la complexation de Gd3+à un dérivé de DPA qui possède une forte affinité pour Zn2+, les deux parties pouvant être indépendamment améliorées (Chem. Eur. J. 2014, 20, 10959-10969).
Dans le but de visualiser les plaques de β-amyloïdes en imagerie multimodale, divers dérivés du compose PiB ont été introduits via différents espaceurs à des chélates de types DO3A. Leur affinité et leur mécanisme d’interaction avec le peptide Aβ1-40, sous forme monomérique ou agrégé, ont été étudiés à travers différentes techniques (SPR, STD-NMR, CD, DLS, TEM). Ces résultats ont mis en évidence que même de faibles différences dans la structure du chélate peuvent avoir des répercussions importantes sur l’agrégation du peptide et, ont plus généralement permis de comprendre le comportement des complexes métalliques possédant une unité ciblante des peptides A β1-40. Bien que les expériences d’immunohistochimie ex vivo sur des tissus de cerveaux humain ayant la maladie d’Alzheimer aient montré la spécificité des sondes métalliques envers les plaques amyloïdes, des biodistributions in vivo avec des analogues de 111In ou de 68Ga ont révélé un passage modéré de la BHE dans la souris, même si un passage 2.5 fois supérieur a été observé dans des souris transgéniques APP/PS1 comparé aux souris de contrôle (coll. C. Geraldes, Coimbra ; Chem. Eur. J. 2015, 21, 5413-5422 ; ACS Med Chem Lett, 2013,4, 436-440).
Sondes IRM à base de complexes de Manganèse. Il y a quelques années, nous avons été parmi les premiers à « redécouvrir » les complexes de Mn2+ comme de potentiels agents de contraste IRM. Plusieurs structures macrocycliques ont été testées afin de déterminer le meilleur compromis entre efficacité IRM, stabilité et inertie cinétique. Nos études de cinétique de dissociation du complexe MnDOTA a apporté la première preuve expérimentale que les complexes de Mn2+ne sont pas tous cinétiquement labiles (Dalton Trans. 2011, 40, 1945-1951). Récemment, nous avons débuté des études sur des complexes de Mn2+ pour lesquels le mécanisme de relaxation est encore peu compris (J. Inorg. Biochemistry, 2016, 154, 50-59).
Sondes théranostiques. Nous combinons IRM et thérapie photodynamique (PDT) à travers une approche moléculaire ou via des nanoparticules. Des chélates de Gd3+ ont été greffés à des photosensibilisateurs de types porphyrines, certains pour une excitation bi-photonique. Nous avons démontré que leur association chimique pouvait être bénéfique à la fois pour les propriétés de relaxation et pour le photosensibilisateur (collab. V. Heitz, Strasbourg ; Chem. Eur. J. 2016, 22, 2775–2786 ; Inorg. Chem. 2016, 55, 4545-4554). Dans une étude de preuve de concept montrant que la PDT peut être induites par des rayons X, nous avons tiré avantage de la luminescence des lanthanides excités par des rayons X pour générer localement de la lumière dans un système micellaire. Ce système comprend des chélates de lanthanides amphiphiles et intègrent l’hypéricine comme photosensibilisateur dans son cœur hydrophobe (figure). Cela contourne les limites intrinsèques de pénétration de la PDT et pourrait être, de façon synergique, combiné avec la radiothérapie classique et le suivi par IRM (collab. M. Réfrégiers, SOLEIL ; Nano Research, 2015, 8, 2373-2379).
B. IRM petit animal
En imagerie, nous développons nos recherches sur des appareils à haut champ (7T et 9.4T) pour compenser la faible sensibilité de la mesure en IRM. Une partie de notre travail consiste donc à développer de nouvelles techniques IRM et SRM spécifiques pour des applications en biologie : il s’agit alors de développer la méthodologie pour la conception de sondes et bobines radiofréquences, pour la conception d’impulsions des séquences ainsi que pour le post-traitement des images IRM (analyse de texture). En IRM, des séquences morphologiques, de perfusion avec agent de contraste, de diffusion (DWI ou DTI), UTE (Ultra Short TE), angiographie, SWI (Susceptibility-Weighted Imaging) ou CEST (Chemical Exchange Saturation Transfert) sont utilisées. En SRM des séquences 1H ou 1H filtrées 13C sont proposées afin d’étudier le métabolisme cérébral et hépatique. Nos études se concentrent sur la caractérisation tissulaire (cérébral, pulmonaire), de pathologies (inflammation, trisomie 21, malaria, cancer, retard de croissance), leur suivi longitudinal, le suivi de l’efficacité d’un traitement ou encore pour l’étude des effets des xénobiotiques sur le cerveau (pesticides, bisphénol A)
1. Etude de l’effet d’une exposition périnatale au bisphénol A (BPA) et à ses dérivés chlorés
Le BPA est un xenoestrogène environnemental auquel l’homme est régulièrement exposé. Les dérivés chlorés du BPA, générés par la désinfection (hypochlorite) de l’eau du robinet montrent une plus grande affinité aux récepteurs des œstrogènes que le BPA. Cependant leurs effets restent inconnus. Comme ils peuvent être détectés dans des embryons humains, nous avons évalué l’effet de l’exposition périnatale au dichloro-BPA sur le cerveau et le foie de souris in vivo par 1H SRM et IRM. Nous avons montré que l’exposition pendant la gestation et la lactation, même à très faible dose, (20 ug / kg / jour) induit des perturbations précoces sur le métabolisme et la microstructure de l’hippocampe ainsi sur la composition des lipides hépatiques sur la descendance. Ces résultats soulèvent des questions sur le risque des dérivés chlorés du BPA sur l’homme (collab. M. Mesnil, Poitiers).
2. Nous avons étudié l’efficacité de nanosondes bimodales (optique et IRM) ciblées, constituées d’un noyau d’oxyde de fer superparamagnétique greffée par covalence avec le fluorochrome NHS-cyanine 5-5, pour le diagnostic de cancer à un stade précoce dans un modèle orthotopique de cancer mammaire. Les résultats de l’IRM ont confirmé l’efficacité de l’immunociblage in vivo de la sonde à la tumeur HER2, ainsi que de son accumulation dans les principaux organes d’élimination (la rate, le foie et les reins). L’imagerie par fluorescence in vivo a, par ailleurs, été corrélée avec les résultats de l’IRM (collab I. Chourpa, E. Vannier, Tours).
3. IRM de diffusion et de perfusion pour l’étude du retard de croissance intra utérin (RCIU) chez la rate
Le modèle animal de RCIU considéré est un modèle de hypoperfusion placentaire par ligature de l’artère utérine chez le rat décrit précédemment par Wigglesworth et al. Les paramètres définis en IRM de perfusion ont montré une diminution du flux sanguin (11 %) et du volume plasmatique (32 %) dans les placentas de foetus atteints par un RCIU. Ils ont également révélé une augmentation de la perméabilité des capillaires du placenta. L’IRM de diffusion DWI a mis en évidence une augmentation de la diffusion du sang dans le placenta (collab. C. Arthuis, Tours).
4. Imagerie de l’inflammation du poumon par IRM du Xe hyperpolarisé
Ce projet vise à étudier l’inflammation pulmonaire par IRM du xénon hyperpolarisé chez la souris. Pour réaliser cette preuve de concept nous avons choisi de cibler la caspase-1, qui est surexprimée lors de la pyroptose des cellules. Une biosonde constituée d’un cryptophane et d’un peptide court sera spécialement synthétisée à cet effet. Les cryptophanes constituent d’excellents transporteurs du xénon dans les milieux biologiques et induisent de forts déplacements chimiques du xénon. Le développement de méthodes rapides d’IRM du xénon-129 hyperpolarisé permettra de suivre la coupure enzymatique de la biosonde et de localiser les cellules ayant subi une pyroptose. (Collab. P. Berthault, Saclay, T. Brotin, Lyon, I. Couillin, Orléans).
Sondes d’imagerie :
- He J., Bonnet C. S., Eliseeva S. V., Lacerda S., Chauvin T., Retailleau P., Szeremeta F., Badet B., Petoud S., Tóth E. and Durand P.
Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities : Visible/Near-Infrared Luminescence, PARACEST- and T1-MRI. J. Am. Chem. Soc. (2016) 138, 2913-2916
- OukhatarF., Meudal H., Landon C., Platas-Iglesias C., Logothetis N. K., Angelovski G., and Tóth E.
Macrocyclic Gd3+ complexes with pendant crown ethers designed for binding zwitter-ionic neurotransmitters. Chem. Eur. J. (2015) 21, 11226-11237
- Bonnet C. S., Caillé F., Pallier A., Morfin J.-F., Petoud S., Suzenet F. and Tóth E.
Mechanistic studies of Gd3+-based MRI contrast agents for Zn2+ detection : towards a rational design. Chem. Eur. J. (2014) 20, 10959-10969
- Carné-Sánchez A., Bonnet C. S., Imaz I., Lorenzo J., Tóth E. and Maspoch D.
Relaxometry Studies of a Highly Stable Nanoscale Metal-Organic Framework made of Cu(II), Gd(III) and the Macrocyclic DOTP. J. Am. Chem. Soc. (2013) 135, 17711-17714
- Lacerda S., Bonnet C. S., Pallier A., Villette S., Foucher F., Westall F., Buron F., Suzenet F., Pichon C., Petoud P. and Tóth E.
Lanthanide-based, near-infrared luminescent and magnetic lipoparticles : monitoring particle integrity. Small (2013) 9, 2662-2666
- Martins A. F., Morfin J.-F., Kubíčková A., Kubíček V., Buron F., Suzenet F., Salerno M., Lazar A. N., Duyckaerts C. , Arlicot N., Guilloteau D., Geraldes C. F. G. C. and Tóth E.
PiB-conjugated, metal-based imaging probes : multimodal approaches for the visualization of β-amyloid plaques. ACS Med Chem Lett. (2013) 4, 436-440
- The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging
edited by A. E. Merbach, L. Helm and É. Tóth. John Wiley & Sons, 2nd edition (2013)
IRM petit animal
- Carrouee A., Allard-Vannier E., Même S., Szeremeta F., Beloeil J. C. and Chourpa I.
Sensitive Trimodal Magnetic Resonance Imaging-Surface-Enhanced Resonance Raman Scattering-Fluorescence Detection of Cancer Cells with Stable Magneto-Plasmonic Nanoprobes. (2015) Analytical Chemistry, 87, 11233-11241
- Sarou-Kanian V., Joudiou N., Louat F., Yon M., Szeremeta F., Même S., Massiot D., Decoville M., Fayon F. and Beloeil J. C.
Metabolite localization in living drosophila using High Resolution Magic Angle Spinning NMR. (2015) Scientific Reports, 5, 9872
- Même S., Joudiou N., Yousfi N., Szeremeta F., Lopes-Pereira P., Beloeil J. C., Herault Y. and Même W
In Vivo 9.4T MRI and 1H MRS for Evaluation of Brain Structural and Metabolic Changes in the Ts65Dn Mouse Model for Down Syndrome. (2014) World Journal of Neuroscience, 4, 152-163
- Mouton-Liger F., Sahún I., Collin T., Lopes Pereira P., Masini D., Thomas S., Paly E., Luilier S., Même S., Jouhault Q., Bennaï S., Beloeil J.-C., Bizot J.-C., Hérault Y., Dierssen M. and Créau N.
Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression : Implications for Down syndrome. (2014) Neurobiology of Disease, 63, 92-106
- Même S., Joudiou N., Szeremeta F., Mispelter J., Louat F., Decoville M., Locker D. and Beloeil J. C.
In vivo magnetic resonance microscopy of drosophila at 9.4T. (2013) Magnetic resonance imaging, 31, 109-119
Membres du groupe thématique
Plissonneau M., Pansieri J., Heinrich-Balard L., Morfin J.-F., Stransky-Heilkron N., Rivory P., Mowat P., Dumoulin M., Cohen R. A., Allémann E., Tóth É., Saraiva M. J., Louis C., Tillement, O., Forge V., Lux F. and Marquette C. M. (2016)
Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-β structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients’ treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [11C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimally-invasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Aβ amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Aβ(1–42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils.
A Theranostic Agent Combining a Two-Photon-Absorbing Photosensitizer for Photodynamic Therapy and a Gadolinium(III) Complex for MRI DetectionChemistry - A European Journal (2016) 22 (8) 2775-2786 - doi : 10.1002/chem.201503433
The convergent synthesis and characterization of a potential theranostic agent, [DPP-ZnP-GdDOTA](-) , which combines a diketopyrrolopyrrole-porphyrin component DPP-ZnP as a two-photon photosensitizer for photodynamic therapy (PDT) with a gadolinium(III) DOTA complex as a magnetic resonance imaging probe, is presented. [DPP-ZnP-GdDOTA](-) has a remarkably high longitudinal water proton relaxivity (19.94 mm(-1) s(-1) at 20 MHz and 25 degrees C) for a monohydrated molecular system of this size. The Nuclear Magnetic Relaxation Dispersion (NMRD) profile is characteristic of slow rotation, related to the extended and rigid aromatic units integrated in the molecule and to self-aggregation occurring in aqueous solution. The two-photon properties were examined and large two-photon absorption cross-sections around 1000 GM were determined between 910 and 940 nm in DCM with 1 % pyridine and in DMSO. Furthermore, the new conjugate was able to generate singlet oxygen, with quantum yield of 0.42 and 0.68 in DCM with 1 % pyridine and DMSO, respectively. Cellular studies were also performed. The [DPP-ZnP-GdDOTA](-) conjugate demonstrated low dark toxicity and was able to induce high one-photon and moderate two-photon phototoxicity on cancer cells.
L-Phosphinothricin modulation of inwardly rectifying K+ channels increased excitability in striatal medium-sized spiny neuronsArchives of Toxicology (2016) 90 (7) 1719–1727 - doi : 10.1007/s00204-016-1721-z Aríñez-Soriano J., Albalad J., Carné-Sánchez A., Bonnet C. S., Busqué F., Lorenzo J., Juanhuixe J., Terban M. W., Imaz I., Tóth É. and Maspoch D. (2016)
pH-responsive relaxometric behaviour of coordination polymer nanoparticles made of a stable macrocyclic gadolinium macrocyclic chelateChemistry - A European Journal (2016) 22 (37) 13162-13170 - doi : 10.1002/chem.201602356
Lanthanide-containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable Gd(III) chelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd-DOTA-4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r1 =16.4 mm(-1) s(-1) at 10 MHz), but also for a pH responsiveness (Δr1 =108 % between pH 4 and 6.5), beyond the values obtained for the low molecular weight Gd-DOTA-4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity.
Four Gadolinium(III) Complexes Appended to a Porphyrin : A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the PhotosensitizeInorganic Chemistry (2016) 55 (9) 4545-4554 - doi : 10.1021/acs.inorgchem.6b00381
A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA]− complexes (DTTA4− = diethylenetriamine-N,N,N″,N″-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 °C, r1 = 43.7 mmol–1 s–1 per gadolinium center, is the highest reported for a bishydrated gadolinium(III)-based contrast agent of medium size and can be related to the rigidity of the molecule. The complex displays also a remarkable singlet oxygen quantum yield of ϕΔ = 0.45 in H2O, similar to that of a meso-tetrasulfonated porphyrin. We also evidenced the ability of the gadolinium(III) conjugate to penetrate in cancer cells with low cytotoxicity. Its phototoxicity on Hela cells was evaluated following incubation at low micromolar concentration and moderate light irradiation (21 J cm–2) induced 50% of cell death. Altogether, these results demonstrate the high potential of this conjugate as a theranostic agent for MRI and PDT.
Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)-Based MRI Contrast Agents with Highly Rigid Open-Chain DerivativesChemistry - A European Journal (2016) 22 (3) 896-901 - doi : 10.1002/chem.201503836
A highly rigid open-chain octadentate ligand (H4 cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6’-[(ethane-1,2 diylbis(carboxymethyl)azanediyl)bis(methylene)]dipicolinic acid (H4 octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd(3+) complex slightly (log KGdL =20.68 vs. 20.23 for [Gd(octapa)](-) ) while other MRI-relevant parameters remain unaffected (one coordinated water molecule ; relaxivity r1 =5.73 mm(-1) s(-1) at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half-life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)](-) (t1/2 =1.49x10(5) h) than for [Gd(octapa)](-) . The kinetic inertness of this novel chelate is superior by 2-3 orders of magnitude compared to non-macrocyclic MRI contrast agents approved for clinical use.
Zhang, W. Y. Martinelli J., Mayer F., Bonnet C. S., Szeremeta F. and Djanashvili K. (2015)
Among the procedures to prepare lanthanide-containing nanoparticles a gap exists in the range between 5 and 40 nm. The miniemulsion technique presented here is intended to fill this discontinuity and offers a facile method that can be applied for the preparation of nanoparticles for various applications, e.g. medical imaging, optics and catalysis. We demonstrate that formation of nanodroplets under emulsion conditions is the key step in the size control of the nanoparticles. The type of surfactant and the nature of the dispersed and continuous phases strongly influence the interfacial activity and, consequently, the size of the final solid particles that result from the subsequent thermal decomposition. Moreover, the choice of the surfactant determines the final elemental composition of the particles, leading to either lanthanide oxides or oxysulfates when using Brij (R) 35 or sodium dodecyl sulfate, respectively. Nanoparticles of holmium and gadolinium were prepared and their applicability as magnetic resonance imaging contrast agents is shown.
Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Abeta amyloid aggregatesJournal of biological inorganic chemistry (2015) 21 (1) 83-99 - doi : 10.1007/s00775-015-1316-9
We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature 17O NMR and NMRD study allowed the assessment of the water exchange rate, k ex 298 = 9.7 x 106 s-1, about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd3+ centers as evidenced by higher relaxivities at 20-60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Abeta1-40 [K d = 194 +/- 11 muM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 +/- 68 M-1 for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Abeta1-40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Abeta1-40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the alpha-helix and beta-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils.
Equilibrium and dissociation kinetics of the Al(NOTA) complex (NOTA=1,4,7-triazacyclononane-1,4,7-triacetate)Reaction Kinetics Mechanisms and Catalysis (2015) 116 (1) 19-33 - doi : 10.1007/s11144-015-0892-6
A detailed investigation of the equilibria and dissociation kinetics for the [Al(NOTA)] complex has been carried out. This complex and its derivatives are known as very good carriers for F-18-isotope in positron emission tomography. The thermodynamic stability of [Al(NOTA)] has been studied by "out of cell" pH-potentiometric technique since the formation rate of the complex is very low in acidic medium. H-1- and Al-27-NMR spectra have been recorded to check the time course of equilibration and to validate the equilibrium model consisting of [Al(NOTA)] with lgK = 17.9(1) and [Al(HNOTA)](+) with lgK(H) = 1.9(3). A metastable mixed hydroxido complex [Al(NOTA)(OH)](-) with lgK(Al(NOTA))(OH) = -12.2(1) was detected in alkaline solution by direct pH-potentiometry, which transforms slowly to [Al(OH)(4)](-). The decomplexation reactions of [Al(NOTA)] have been investigated in both acidic and basic conditions. The rate of dissociation is extremely low in acidic medium, while in alkaline solution, it can be characterized by the rate law k(obs) = k(0) + k(1) [OH-], where k(0) = (2.0 +/- 0.1) 9 10(-6) s(-1) and k(1) = (6.8 +/- 0.5) 9 10(-6) M-1 s(-1). The formation of the ternary [Al(NOTA)(F)](-) complex via direct reaction of [Al(NOTA)] and F- cannot be detected by either fluoride selective electrode or by F-19-NMR spectroscopy. However, by applying solvent mixture (1 : 1 ethanol : water) and heating, the ternary [Al(NOTA)(F)](-) complex was found to form quantitatively within 15 minutes.
PURPOSE : The aim of this work is to develop an efficient and fully automated radiosynthesis of three derivatives of the Pittsburgh compound B labeled with gallium-68 for the detection of amyloid plaques. PROCEDURES : The radiolabeling of the precursors and purification of the radiolabeled agents by high pressure liquid chromatography has been studied prior to their in vitro and in vivo evaluations. RESULTS : The complete process led, in 50 min, to pure Ga-68 products in a 12-38 % yield and with appreciable specific radioactivity (SRA, 85-168 GBq/mumol) which enabled us to demonstrate a considerable in vivo stability of the products. Unfortunately, this result was associated with a poor blood-brain barrier (BBB) permeability and a limited uptake of our compounds by amyloid deposits was observed by in vitro autoradiography. CONCLUSION : Although we have not yet identified a compound able to significantly mark cerebral amyloidosis, this present investigation will likely contribute to the development of more successful Ga-68 radiotracers.
Sensitive Trimodal Magnetic Resonance Imaging-Surface-Enhanced Resonance Raman Scattering-Fluorescence Detection of Cancer Cells with Stable Magneto-Plasmonic NanoprobesAnalytical Chemistry (2016) 87 (22) 11233-11241 - doi : 10.1021/acs.analchem.5b02419
Novel magneto-plasmonic nanoprobes were designed for multimodal diagnosis of cancer by combination of magnetic resonance imaging (MRI), surface-enhanced resonance Raman scattering (SERRS), and fluorescence emission in the very near infrared (VNIR). A controlled electrostatic assembly of silver nanoparticles (AgNPs), super-paramagnetic iron oxide nanopartides (SPIONs), VNIR dye Nile Blue (NB), and biopolymer chitosan (Chi) was used to formulate the AgIONs-Chi nanoprobes. The formulation protocol did not involve organic solvents and was rapid and efficient as confirmed by magnetic sorting. The SERRS response of the nanoprobes was very intense and constant for days. It decreased linearly upon 1000-fold dilution and was still recognizable at 0.1 nM NB concentration. After 30 days of storage, the SERRS loss was less than 30% and the hydrodynamic size of the AgIONs-Chi in PBS remained below 200 nm. The gradual decrease of the ratio SERRS/fluorescence allowed one to monitor the release of the fluorescent molecule upon long-term nanoprobe dissociation. The AgIONs-Chi exhibited 2-fold higher MRI contrast than that of commercially available SPION suspensions. Finally, the nanoprobes were actively uptaken by HeLa cancer cells and ensured trimodal MRI-SERRS-fluorescence detection of 10 itL cell inclusions in cm-sized agarose gels used here as phantom models of microtumors. The above results show that the magneto-plasmonic AgIONs-Chi are promising substrates for SERRS analysis in solution and for multimodal imaging of cancer cells.
Macrocyclic Gd(3+) Complexes with Pendant Crown Ethers Designed for Binding Zwitterionic NeurotransmittersChemistry - A European Journal (2015) 21 (31) 11226-11237 - doi : 10.1002/chem.201500542
A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1) s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.
A Pyridine-Based Ligand with Two Hydrazine Functions for Lanthanide Chelation : Remarkable Kinetic Inertness for a Linear, Bishydrated ComplexInorganic Chemistry (2015) 54 (12) 5991-6003 - doi : 10.1021/acs.inorgchem.5b00804
To study the influence of hydrazine functions in the ligand skeleton, we designed the heptadentate HYD ligand (2,2’,2″,2‴-(2,2’-(pyridine-2,6-diyl)bis(2-methylhydrazine-2,1,1-triyl)) tetraacetic acid) and compared the thermodynamic, kinetic, and relaxation properties of its Ln(3+) complexes to those of the parent pyridine (Py) analogues without hydrazine (Py = 2,6-pyridinebis(methanamine)-N,N,N’,N’-tetraacetic acid). The protonation constants of HYD were determined by pH-potentiometric measurements, and assigned by a combination of UV-visible and NMR spectroscopies. The protonation sequence is rather unusual and illustrates that small structural changes can strongly influence ligand basicity. The first protonation step occurs on the pyridine nitrogen in the basic region, followed by two hydrazine nitrogens and the carboxylate groups at acidic pH. Contrary to Py, HYD self-aggregates through a pH-dependent process (from pH ca. 4). Thermodynamic stability constants have been obtained by pH-potentiometry and UV-visible spectrophotometry for various Ln(3+) and physiological cations (Zn(2+), Ca(2+), Cu(2+)). LnHYD stability constants show the same trend as those of LnDTPA complexes along the Ln(3+) series, with log K = 18.33 for Gd(3+), comparable to the Py analogue. CuHYD has a particularly high stability (log K > 19) preventing its determination from pH-potentiometric measurements. The stability constant of CuPy was also revisited and found to be underestimated in previous studies, highlighting that UV-visible spectrophotometry is often indispensable to obtain reliable stability constants for Cu(2+) chelates. The dissociation of GdL, assessed by studying the Cu(2+)-exchange reaction, occurs mainly via an acid-catalyzed process, with limited contribution from direct Cu(2+) attack. The kinetic inertness of GdHYD is remarkable for a linear bishydrated chelate ; the 25-fold increase in the dissociation half-life with respect to the monohydrated commercial contrast agent GdDTPA (t1/2 = 5298 h for GdHYD vs 202 h for GdDTPA) is related to the rigidity of the HYD ligand due to the pyridine and methylated hydrazine functions of the backbone. A combined analysis of variable-temperature (17)O NMR and NMRD data on GdHYD yielded the microscopic parameters influencing relaxation properties. The high relaxivity (r1 = 7.7 mM(-1) s(-1) at 20 MHz, 25 °C) results from the bishydrated character of the complex combined with an optimized water exchange rate (kex(298) = 7.8 × 10(6) s(-1)). The two inner-sphere water molecules are not replaced through interaction with biological cations such as carbonate, citrate, and phosphate as monitored by (1)H relaxivity and luminescence lifetime measurements.
Stabilizing Divalent Europium in Aqueous Solution Using Size-Discrimination and Electrostatic EffectsInorganic Chemistry (2015) 54 (10) 4940-4952 - doi : 10.1021/acs.inorgchem.5b00548
We report two macrocyclic ligands containing a 1,10-diaza-18-crown-6 fragment functionalized with either two picolinamide pendant arms (bpa18c6) or one picolinamide and one picolinate arm (ppa18c6(-)). The X-ray structure of [La(ppa18c6)(H2O)](2+) shows that the ligand binds to the metal ion using the six donor atoms of the crown moiety and the four donor atoms of the pendant arms, 11-coordination being completed by the presence of a coordinated water molecule. The X-ray structure of the [Sr(bpa18c6)(H2O)](2+) was also investigated due to the very similar ionic radii of Sr(2+) and Eu(2+). The structure of this complex is very similar to that of [La(ppa18c6)(H2O)](2+), with the metal ion being 11-coordinated. Potentiometric measurements were used to determine the stability constants of the complexes formed with La(3+) and Eu(3+). Both ligands present a very high selectivity for the large La(3+) ion over the smaller Eu(3+), with a size-discrimination ability that exceeds that of the analogous ligand containing two picolinate pendant arms reported previously (bp18c6(2-)). DFT calculations using the TPSSh functional and the large-core pseudopotential approximation provided stability trends in good agreement with the experimental values, indicating that charge neutral ligands derived from 1,10-diaza-18-crown-6 enhance the selectivity of the ligand for the large Ln(3+) ions. Cyclic voltammetry measurements show that the stabilization of Eu(2+) by these ligands follows the sequence bp18c6(2-) < ppa18c6(-) < bpa18c6 with half-wave potentials of -753 mV (bp18c6(2-)), -610 mV (ppa18c6(-)), and -453 mV (bpa18c6) versus Ag/AgCl. These values reveal that the complex of bpa18c6 possesses higher stability against oxidation than the aquated ion, for which an E1/2 value of -585 mV has been measured.
The acyclic ligand octapa(4-) (H4octapa = 6,6’-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid) forms stable complexes with the Ln(3+) ions in aqueous solution. The stability constants determined for the complexes with La(3+), Gd(3+), and Lu(3+) using relaxometric methods are log KLaL = 20.13(7), log KGdL = 20.23(4), and log KLuL = 20.49(5) (I = 0.15 M NaCl). High stability constants were also determined for the complexes formed with divalent metal ions such as Zn(2+) and Cu(2+) (log KZnL = 18.91(3) and log KCuL = 22.08(2)). UV-visible and NMR spectroscopic studies and density functional theory (DFT) calculations point to hexadentate binding of the ligand to Zn(2+) and Cu(2+), the donor atoms of the acetate groups of the ligand remaining uncoordinated. The complexes formed with the Ln(3+) ions are nine-coordinated thanks to the octadentate binding of the ligand and the presence of a coordinated water molecule. The stability constants of the complexes formed with the Ln(3+) ions do not change significantly across the lanthanide series. A DFT investigation shows that this is the result of a subtle balance between the increased binding energies across the 4f period, which contribute to an increasing complex stability, and the parallel increase of the absolute values of the hydration free energies of the Ln(3+) ions. In the case of the [Ln(octapa)(H2O)](-) complexes the interaction between the amine nitrogen atoms of the ligand and the Ln(3+) ions is weakened along the lanthanide series, and therefore the increased electrostatic interaction does not overcome the increasing hydration energies. A detailed kinetic study of the dissociation of the [Gd(octapa)(H2O)](-) complex in the presence of Cu(2+) shows that the metal-assisted pathway is the main responsible for complex dissociation at pH 7.4 and physiological [Cu(2+)] concentration (1 muM).
We have developed new methods enabling in vivo localization and identification of metabolites through their (1)H NMR signatures, in a drosophila. Metabolic profiles in localized regions were obtained using HR-MAS Slice Localized Spectroscopy and Chemical Shift Imaging at high magnetic fields. These methods enabled measurement of metabolite contents in anatomic regions of the fly, demonstrated by a decrease in beta-alanine signals in the thorax of flies showing muscle degeneration.
We report lanthanide-based micelles integrating hypericin (Hyp) for X-raytriggered photodynamic therapy (PDT). The lanthanide luminescence induced by X-ray irradiation excites the photosensitizer, which leads to the generation of singlet oxygen. This versatile approach can be extended to other photosensitizers or other types of liponanoparticles and can allow for magnetic resonance imaging (MRI) guidance.
Interaction of PiB-Derivative Metal Complexes with Beta-Amyloid Peptides : Selective Recognition of the Aggregated FormsChemistry – A European Journal (2015) 21 (14) 5413-5422 - doi : 10.1002/chem.201406152
Metal complexes are increasingly explored as imaging probes in amyloid peptide related pathologies. We report the first detailed study on the mechanism of interaction between a metal complex and both the monomer and the aggregated form of Aβ1–40 peptide. We have studied lanthanide(III) chelates of two PiB-derivative ligands (PiB=Pittsburgh compound B), L1 and L2, differing in the length of the spacer between the metal-complexing DO3A macrocycle (DO3A= 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and the peptide-recognition PiB moiety. Surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy revealed that they both bind to aggregated Aβ1–40 (KD=67–160 μM), primarily through the benzothiazole unit. HSQC NMR spectroscopy on the 15N-labeled, monomer Aβ1–40 peptide indicates nonsignificant interaction with monomeric Aβ. Time-dependent circular dichroism (CD), dynamic light scattering (DLS), and TEM investigations of the secondary structure and of the aggregation of Aβ1–40 in the presence of increasing amounts of the metal complexes provide coherent data showing that, despite their structural similarity, the two complexes affect Aβ fibril formation distinctly. Whereas GdL1, at higher concentrations, stabilizes β-sheets, GdL2 prevents aggregation by promoting α-helical structures. These results give insight into the behavior of amyloid-targeted metal complexes in general and contribute to a more rational design of metal-based diagnostic and therapeutic agents for amyloid- associated pathologies.
Molecular magnetic resonance imaging (MRI) approaches that detect biomarkers associated with neural activity would allow more direct observation of brain function than current functional MRI based on blood-oxygen-level-dependent contrast. Our objective was to create a synthetic molecular platform with appropriate recognition moieties for zwitterionic neurotransmitters that generate an MR signal change upon neurotransmitter binding. The gadolinium complex (GdL) we report offers ditopic binding for zwitterionic amino acid neurotransmitters, via interactions (i) between the positively charged and coordinatively unsaturated metal center and the carboxylate function and (ii) between a triazacrown ether and the amine group of the neurotransmitters. GdL discriminates zwitterionic neurotransmitters from monoamines. Neurotransmitter binding leads to a remarkable relaxivity change, related to a decrease in hydration number. GdL was successfully used to monitor neural activity in ex vivo mouse brain slices by MRI.
Morfin J.-F., Beloeil J.-C., Toth E. (2014)
L’imagerie par résonance magnétique (IRM) est maintenant entrée dans la vie courante, la moindre blessure aux sports d’hiver conduit à passer une IRM. Son caractère atraumatique et non invasif constitue un avantage décisif. La majorité des hôpitaux en sont équipés. L’IRM ne nécessite pas obligatoirement l’utilisation d’agents d’imagerie pour fournir une image structurelle de l’intérieur de l’organisme. Les réglages physiques de l’expérimentation permettent même d’accéder à différents paramètres des tissus (détection de tumeurs, oedèmes...). Ce n’est que si l’on veut aller plus loin dans la spécificité de la détection, qu’il est intéressant et même indispensable de faire appel à des agents de contraste injectables, même si l’on perd alors partiellement le caractère non invasif de l’IRM. Comme nous allons le montrer, la complexité des molécules va de l’agent chimiquement non spécifique jusqu’à l’agent de contraste dit « intelligent » (smart agent).
A Bis(pyridine N-oxide) Analogue of DOTA : Relaxometric Properties of the Gd-III Complex and Efficient Sensitization of Visible and NIR-Emitting Lanthanide(III) Cations Including Pr-III and Ho-IIIChemistry-a European Journal (2015) 20 (45) 14834-14845 - doi : 10.1002/chem.201403856
We report the synthesis of a cyclen-based ligand (4,10-bis[(1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid = L1) containing two acetate and two 2-methylpyridine N-oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the Gd-III complex may be sufficient for biological applications. A detailed structural study of the complexes by H-1 NMR spectroscopy and DFT calculations indicates that they adopt an anti-Delta(lambda lambda lambda lambda) conformation in aqueous solution, that is, an anti-square antiprismatic (anti-SAP) isomeric form, as demonstrated by analysis of the H-1 NMR paramagnetic shifts induced by Yb-III. The water-exchange rate of the Gd-III complex is k(ex)(298) = 6.7 x 10(6) s(-1), about a quarter of that for the mono-oxidopyridine analogue, but still about 50% higher than the k(ex)(298) of GdDOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The 2-methylpyridine N-oxide chromophores can be used to sensitize a wide range of Ln(III) ions emitting in both the visible (Eu-III and Tb-III) and NIR (Pr-III, Nd-III, Ho-III, Yb-III) spectral regions. The emission quantum yield determined for the Yb-III complex (Q(Yb)(L) = 7.3(1) x 10(-3)) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.
A series of novel pyridine-based Gd3+ complexes have been prepared and studied as potential MRI contrast agents for Zn2+ detection. By independent assessment of molecular parameters affecting relaxivity, we could interpret the relaxivity changes observed upon Zn2+ binding in terms of variations of the rotational motion.
Selectively functionalized cyclodextrins with a bodipy fluorescent tag or Gd3+ complex were synthetized and threaded onto a polyammonium chain to form polyrotaxanes. This modular supramolecular assembly makes an ideal platform for bimodal (fluorescent and MRI) imaging applications.
Nanozeolite-LTL with Gd-III Deposited in the Large and Eu-III in the Small Cavities as a Magnetic Resonance Optical Imaging ProbeChemistry - A European Journal (2014) 20 (12) 3358-3364 - doi : 10.1002/chem.201304457
The immense structural diversity of more than 200 known zeolites is the basis for the wide variety of applications of these fascinating materials ranging from catalysis and molecular filtration to agricultural uses. Despite this versatility, the potential of zeolites in medical imaging has not yet been much exploited. In this work a novel strategy is presented to selectively deposit different ions into distinct framework locations of zeolite-LTL (Linde type L) and it is demonstrated that the carefully ion-exchanged Gd/Eu-containing nanocrystals acquire exceptional magnetic properties in combination with enhanced luminescence. This smart exploitation of the framework structure yields the highest relaxivity density (13.7s(-1)Lg(-1) at 60MHz and 25 degrees C) reported so far for alumosilicates, rendering these materials promising candidates for the design of dual magnetic resonance/optical imaging probes, as demonstrated in preliminary phantom studies.
We report the synthesis of two ligands containing a DO3A unit (H(3)DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) linked to a triazacyclononane (TACN) moiety by a 2,6-dimethylpyridine spacer designed to form stable Ln(3+) complexes in solution that respond to the presence of Zn2+ ions. The Eu3+ and Gd3+ complexes have been characterized by using a combination of experimental and theoretical techniques that include absorption and emission electronic spectroscopy, NMR spectroscopy, H-1 relaxometry, and DFT calculations. The Ln(3+) ions are eight-coordinated by the ligand, which binds to the metal ion through the seven donor atoms of the DO3A unit and the nitrogen atom of the pyridyl linker. Luminescence lifetime measurements recorded from solutions of the Eu3+ complexes in H2O and D2O and relaxometric measurements point to the absence of inner-sphere water molecules. The addition of Zn2+ causes important changes in the absorption spectra of the complexes that evidence the formation of both 1:1 and 2:1 (Ln(3+)/Zn2+) complex species. However, the emission lifetimes of the Eu3+ complexes and relaxivity experience weak changes, thus indicating that Zn2+ addition does not significantly affect the number of coordinated water molecules. The Gd3+ complexes show a weak emission band at 325 nm, the intensity of which dramatically increases in the presence of Zn2+. However, the turn-on behaviour induced by Zn2+ is not observed for other metal cations such as Ca2+, Mg2+ or Cu2+. DFT calculations indicate that a photoinduced electron-transfer (PET) process is responsible for the quenching of the luminescence in the absence of Zn2+.
In an effort towards the visualization of β-amyloid (Aβ) plaques by T 1-weighted magnetic resonance imaging for detection of Alzheimer’s disease, we report the synthesis and characterization of stable, noncharged Gd(3+) complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aβ plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol-water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00-1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined (17)O NMR and (1)H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari-Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Aβ1-40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with K A values ranging between 250 and 910 M(-1).
Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy.
Ligand Design in Medicinal Inorganic Chemistry presents the state-of-the-art in ligand design for medicinal inorganic chemistry applications. Each individual chapter describes and explores the application of compounds that either target a disease site, or are activated by a disease-specific biological process.
Teng F., Beray-Berthat V., Coqueran B., Lesbats C., Kuntz M., Palmier B., Garraud M., Bedfert C., Slane N., Berezowski V., Szeremeta F., Hachani J., Scherman D., Plotkine M., Doan B. T., Marchand-Leroux C. and Margaill I. (2013)
Prevention of rt-PA induced blood-brain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in miceExperimental neurology (2013) 248, 416-428 - doi : 10.1016/j.expneurol.2013.07.007
Recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke, but its administration aggravates the risk of hemorrhagic transformations. Experimental data demonstrated that rt-PA increases the activity of poly(ADP-ribose)polymerase (PARP). The aim of the present study was to investigate whether PJ34, a potent (PARP) inhibitor, protects the blood-brain barrier components from rt-PA toxicity. In our mouse model of cerebral ischemia, administration of rt-PA (10 mg/kg, i.v.) 6h after ischemia aggravated the post-ischemic degradation of ZO-1, claudin-5 and VE-cadherin, increased the hemorrhagic transformations (assessed by brain hemoglobin content and magnetic resonance imaging). Furthermore, rt-PA also aggravated ischemia-induced functional deficits. Combining PJ34 with rt-PA preserved the expression of ZO-1, claudin-5 and VE-cadherin, reduced the hemorrhagic transformations and improved the sensorimotor performances. In vitro studies also demonstrated that PJ34 crosses the blood-brain barrier and may thus exert its protective effect by acting on endothelial and/or parenchymal cells. Thus, co-treatment with a PARP inhibitor seems to be a promising strategy to reduce rt-PA-induced vascular toxicity after stroke.
Relaxometry studies of a highly stable nanoscale metal-organic framework made of Cu(II), Gd(III), and the macrocyclic DOTPJournal of the American Chemical Society (2013) 135 (47) 17711-17714 - doi : 10.1021/ja4094378
The macrocyclic ligand DOTP is used to assemble a porous, heterometallic metal-organic framework (MOF). This MOF is miniaturizable down to the nanoscale to form stable colloids, is stable in physiological saline solution and cell culture media, and is not cytotoxic. It shows interesting relaxometric properties with r1 at high field (500 MHz) of 5 mM(-1).s(-1) and a maximum r1 = 15 mM(-1).s(-1) at 40 MHz, which remains constant over a wide pH range and increases with temperature.
PiB-Conjugated, Metal-Based Imaging Probes : Multimodal Approaches for the Visualization of β‑Amyloid PlaquesACS Medicinal Chemistry Letters 4 (5) 436-440
In an effort toward the visualization of β-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a ell-established marker of Aβ plaques, to DO3A-monoamide that is capable of forming stable, noncharged complexes with different trivalent metal ions including Gd3+ for MRI and 111In3+ for SPECT applications. Proton relaxivity measurements evidenced binding of d(DO3A-PiB) to the amyloid peptide Aβ1−40 and to human serum albumin, resulting in a two- and four-fold relaxivity increase, respectively. Ex vivo immunohistochemical studies showed that the DO3A-PiB complexes selectively target Aβ plaques on zheimer’s disease human brain tissue. Ex vivo biodistribution data obtained for the 111In-analogue pointed to a moderate blood−brain barrier (BBB) penetration in adult male Swiss mice (without amyloid deposits) with 0.36% ID/g in the cortex at 2 min postinjection.
Due to its favorable relaxometric properties, Mn(2+) is an appealing metal ion for magnetic resonance imaging (MRI) contrast agents. This paper reports the synthesis and characterization of three new triazadicarboxylate-type ligands and their Mn(2+) chelates (NODAHep, 1,4,7-triazacyclononane-1,4-diacetate-7-heptanil ; NODABA, 1,4,7-triazacyclononane-1,4-diacetate-7-benzoic acid ; and NODAHA, 1,4,7-triazacyclononane-1,4-diacetate-7-hexanoic acid). The protonation constants of the ligands and the stability constants of the chelates formed with Mn(2+) and the endogenous Zn(2+) ion have been determined by potentiometry. In overall, the thermodynamic stability of the chelates is lower than that of the corresponding NOTA analogues (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetate), consistent with the decreased number of coordinating carboxylate groups. Variable temperature (1)H NMRD and (17)O NMR measurements have been performed on the paramagnetic chelates to provide information on the water exchange rates and the rotational dynamics. The values of the (17)O chemical shifts are consistent with the presence of one water molecule in the first coordination sphere of Mn(2+). The three complexes are in the slow to intermediate regime for the water exchange rate, and they all display relatively high rotational correlation times, which explain the relaxivity values between 4.7 and 5.8 mM(-1) s(-1) (20 MHz and 298 K). These relaxivities are higher than expected for Mn(2+) chelates of such size and comparable to those of small monohydrated Gd(3+) complexes. The amphiphilic [Mn(NODAHep)] forms micelles above 22 mM (its critical micellar concentration was determined by relaxometry and fluorescence), and interacts with HSA via its alkylic carbon chain providing a 60% relaxivity increase at 20 MHz due to a longer tumbling time.
New tris-3,4-HOPO lanthanide complexes as potential imaging probes : complex stability and magnetic propertiesDalton Transactions 42 (17) 6046-6057
There is a growing interest in the development of new medical diagnostic tools with higher sensibility and less damage for the patient body, namely on imaging reporters for the management of diseases and optimization of treatment strategies. This article examines the properties of a new class of lanthanide complexes with a tripodal tris-3-hydroxy-4-pyridinone (tris-3,4-HOPO) ligand - NTP(PrHP)3. Among the studies herein performed, major relevance is given to the thermodynamic stability of the complexes with a series of Ln(3+) ions (Ln = La, Pr, Gd, Er, Lu) and to the magnetic relaxation properties of the Gd(3+) complex. This hexadentate ligand enables the formation of (1 : 1) Ln(3+) complexes with high thermodynamic stability following the usual trend, while the Gd-chelates show improved relaxivity (higher hydration number), as compared with the commercially available Gd-based contrast agents (CAs) ; transmetallation of the Gd(3+)-L complex with Zn(2+) proved to be thermodynamically and kinetically disfavored. Therefore, NTP(PrHP)3 emerges as part of a recently proposed new generation of CAs with prospective imaging sensibility gains.
Lanthanide-Based, Near-Infrared Luminescent and Magnetic Lipoparticles : Monitoring Particle IntegritySmall (2013) 9 (16) 2662-2666 - doi : 10.1002/smll.201201923
Near-infrared emitting, magnetic particles for combined optical and MR detection based on liposomes or artificial lipoproteins are presented. They provide a novel strategy for the luminescence sensitization of lanthanide cations (Yb3+, Nd3+) without covalent bonds between the chromophore and the lanthanide, and provide an unambiguous tool for monitoring the integrity of the liponanoparticles, via emission in the NIR region.
Amide conjugates of the DO3A-N-(α-amino)propionate ligand : leads for stable, high relaxivity contrast agents for MRI ?Contrast Media Mol Imaging 8 (1) 40-49
A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents.
Bonnet, C.S. and Tóth, E. (2012)
Magnetic resonance imaging is one of the most efficient diagnostic modalities in clinical radiology and biomedical research. To enhance image contrast, paramagnetic complexes, mainly Gd3+ chelates, are used. In recent years, molecular imaging has emerged as a new area aiming at noninvasive visualization of expression and function of bioactive molecules at the cellular level. This chapter is devoted to the description of supramolecular approaches in the development of highly efficient and smart contrast agents. We demonstrate via representative examples (micellar systems, liposomes, protein-bound chelates, etc.) how supramolecular approaches are applied to increase the efficacy of Gd3+-based contrast agents. We also include an introduction to chemical exchange saturation transfer (CEST) agents and show how supramolecular systems, such as liposomes, can be beneficial to decrease the sensitivity limit of CEST detection. Supramolecular assemblies offer an important advantage regarding the metabolic fate. While covalent polymers are excreted slowly from the body, supramolecular systems facilitate the body elimination via the excretion pathway of the small constituents. Finally, we discuss molecular imaging probes that provide an MRI response mainly through the modulation of supramolecular interactions to various biochemical variables, such as pH, temperature, metal ions, and enzymes.
A new macrocyclic ligand, N,N’-bis[(6-carboxy-2-pyridyl)methyl]-2,11-diaza[3.3](2,6)pyridinophane (H(2)BPDPA), was prepared, and its coordination properties toward the Ln(III) ions were investigated. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that they contain one inner-sphere water molecule. The structure of the complexes in solution has been investigated by (1)H and (13)C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (B3LYP) level. The minimum-energy conformation calculated for the Yb(III) complex is in excellent agreement with the experimental structure in solution, as demonstrated by analysis of the Yb(III)-induced paramagnetic (1)H shifts. Nuclear magnetic relaxation dispersion (NMRD) profiles and (17)O NMR measurements recorded on solutions of the Gd(III) complex were used to determine the parameters governing the relaxivity. The results show that this system is endowed with a relatively fast water-exchange rate k(ex)(298) = 63 × 10(6) s(-1). Thermodynamic stability constants were determined by pH-potentiometric titration at 25 °C in 0.1 M KCl. The stability constants, which fall within the range logK(LnL) = 12.5-14.2, point to a relatively low stability of the complexes primarily as a consequence of the low basicity of the ligand.
Mn2+ has five unpaired d electrons, a long electronic relaxation time, and labile water exchange, which make it an attractive alternative to Gd3+ in the design of contrast agents for medical Magnetic Resonance Imaging. In order to ensure in vivo safety and high contrast agent efficiency, the Mn2+ ion has to be chelated by a ligand that provides high thermodynamic stability and kinetic inertness of the complex and has to have at least one free coordination site for a water molecule. Unfortunately, these two requirements are contradictory, as lower denticity of the ligands, which leads to more inner-sphere water molecules often implies a decreased stability of the complex, and, therefore, it is necessary to find a balance between both requirements. In the last decade, a large amount of experimental data has been collected to characterize the physico-chemical properties of Mn2+ chelates with variable ligand structures. They now allow for establishing trends of how the ligand structure, the rigidity of the ligand scaffold, and its donor–acceptor properties influence the thermodynamic, kinetic, and redox stability of the Mn2+ complex. This microreview surveys the current literature in this field.
Lanthanide Complexes Formed with the Tri- and Tetraacetate Derivatives of Bis(aminomethyl)phosphinic Acid : Equilibrium, Kinetic and NMR Spectroscopic StudiesEuropean Journal of Inorganic Chemistry 2012 (12) 2062–2073
The lanthanide(III) complexes formed with the tri- and tetraacetate derivatives of bis(aminomethyl)phosphinic acid, L1 and L2, respectively, have been studied by pH potentiometry, spectrophotometry and 1H and 17O NMR spectroscopy. L1 forms [Ln(L1)]–, [Ln(L1)2]4–, protonated [Ln(HL1)] and Ln(H2L1)]+, and [Ln(L1)(OH)]2– hydroxido complexes. Heptadentate L2 forms [Ln(L2)]2– and protonated [Ln(HL2)]– and [Ln(H2L2)] complexes in solution and it shows a strong propensity to form [Ln2(L2)]+ dinuclear complexes, which has not been observed previously. The stability constants (log KLnL) of the complexes increase in the order [Ln(L1)]– < [Ln(L2)]2– following the order of increasing number of acetate pendants attached to the bis(aminomethyl)phosphinic acid (BAP) backbone. Within the LnIII series, the log KLnL values increase from La3+ to Gd3+ and remain practically constant for the heavier lanthanides. Despite the lower basicity, the ligands that contain a phosphinate group generally form similar (L1) or more stable (L2) Ln3+ complexes than the structurally similar N-benzylethylenediamine-N,N′,N′-triacetic acid (L3) and propylenediamine-N,N,N′,N′-tetraacetic acid (L4), respectively. This indicates that the hard phosphinate group may be coordinated to the Ln3+ ions in the complexes, whereas the larger negative charge of the BAP derivatives may also have an extra stabilizing effect. The kinetic inertness of [Ln(L1)] and [Ln(L2)] is lower than that of similar [Ln(EDTA)]– (EDTA = ethylenediamine-N,N,N′,N′-tetraacetic acid), but the rate constants that characterize the dissociation of [Ln(L2)]2– are at least two orders of magnitude lower than those obtained for [Ln(L4)]–. Variable-temperature 17O transverse and longitudinal relaxation rates and NMR spectroscopic chemical shifts have been measured to assess the water exchange and rotational dynamics of [Gd(L2)]. The chemical shifts evidenced monohydration of the complex. The water exchange rate, kex298 = (2.7 ± 0.4) × 107 s–1 is about ten times higher than that of [Ln(DTPA)]2– (DTPA = diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid). The rotational correlation time, τRO298 = 270 ± 30 ps, is long considering the small size of the chelate, which points to aggregation in aqueous solution, in accordance with the high value of the proton relaxivity measured.
Tris(phosphonomethyl)cyclen Derivatives : Thermodynamic Stability, Kinetics, Solution Structure, and Relaxivity of Ln(3+) ComplexesEuropean Journal of Inorganic Chemistry 2012 (15) 2548-2559
The lanthanide (Ln3+) complexes of three cyclen-based ligands containing three methylphosphonate pendant arms were studied, the ligands being 1,4,7,10-tetraazacyclododecane-1,4,7-triyltris(methylphosphonic acid) (H6do3p), 3-[4,7,10-tris(phosphonomethyl)-1,4,7,10-tetraazacyclododec-1-yl]propanoic acid (H7do3p1pr), and 10-(3-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyltris(methylphosphonic acid) (H6do3p1ol). The three macrocyclic ligands form complexes of very high thermodynamic stability with all studied Ln3+ ions. Kinetic studies showed that the acid-assisted dissociation of Ce3+ complexes of these ligands is much faster than for the complex of the related ligand H8dotp [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayltetrakis(methylphosphonic acid)]. The number of water molecules coordinated to the Eu3+ and Gd3+ complexes was estimated to be < 1 for the do3p1ol ligand but ca. 1 for the other two ligands, as obtained by time-resolved luminescence spectroscopy and by 1H and 17O relaxometric measurements. The NMR spectroscopic data indicate the existence of a considerable contribution from second-sphere water molecules to the relaxivity of all the Gd3+ complexes studied. The 1H and 31P NMR spectra of the Eu3+, Yb3+ and Lu3+ complexes showed that the propionate arm in the [Ln(do3p1pr)]4 complexes and the propanol arm in the [Ln(do3p1ol)]3 complexes are not bound to the Ln3+ ion. The [Ln(do3p)]3 and [Ln(do3p1pr)]4 complexes have a clear preference for the TSAP (twisted square antiprismatic) isomer, while both SAP (square antiprismatic) and TSAP isomers are present in solutions of the [Ln(do3p1ol)]3 complexes.
In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-infrared emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, L1, L2 and L3, have been synthesized and the corresponding Gd(3+), Nd(3+) and Yb(3+) complexes investigated. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biological applications and (ii) are able to emit a sufficient number of photons to ensure sensitive NIR detection for microscopic imaging. Here we report the first observation of a NIR signal arising from a Ln(3+) complex in aqueous solution in a microscopy setup. The lanthanide complexes have high thermodynamic stability (log K(LnL) =17.7-18.7) and good selectivity for lanthanide ions versus the endogenous cations Zn(2+), Cu(2+), and Ca(2+) thus preventing transmetalation. A variable temperature and pressure (17)O NMR study combined with nuclear magnetic relaxation dispersion measurements yielded the microscopic parameters characterizing water exchange and rotation. Bishydration of the lanthanide cation in the complexes, an important advantage to obtain high relaxivity for the Gd(3+) chelates, has been demonstrated by (17)O chemical shifts for the Gd(3+) complexes and by luminescence lifetime measurements for the Yb(3+) analogues. The water exchange on the three Gd(3+) complexes is considerably faster (k(ex)(298) = (13.9-15.4) × 10(6) s(-1)) than on commercial Gd(3+)-based contrast agents and proceeds via a dissociative mechanism, as evidenced by the large positive activation volumes for GdL1 and GdL2 (+10.3 ± 0.9 and +10.6 ± 0.9 cm(3) mol(-1), respectively). The relaxivity of GdL1 is doubled at 40 MHz and 298 K in fetal bovine serum (r(1) = 16.1 vs 8.5 mM(-1) s(-1) in HEPES buffer), due to hydrophobic interactions between the chelate and serum proteins. The isoquinoline core allows for the optimization of the optical properties of the luminescent lanthanide complexes in comparison to the pyridinic analogues and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biological applications. L2 and L3 bear two methoxy substituents on the aromatic core in ortho and para positions, respectively, that further modulate their electronic structure. The Nd(3+) and Yb(3+) complexes of the ligand L3, which incorporates the p-dimethoxyisoquinoline moiety, can be excited up to 420 nm. This wavelength is shifted over 100 nm toward lower energy in comparison to the pyridine-based analogue. The luminescence quantum yields of the Nd(3+) (0.013-0.016%) and Yb(3+) chelates (0.028-0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water molecules. More importantly, the 980 nm NIR emission band of YbL3 was detected with a good sensitivity in a proof of concept microscopy experiment at a concentration of 10 μM in fetal bovine serum. Our results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient number of photons to ensure sensitive detection in practical applications. In particular, these ligands containing an aromatic core with coordinating pyridine nitrogen can be easily modified to tune the optical properties of the NIR luminescent lanthanide complexes while retaining good complex stability and MRI characteristics for the Gd(3+) analogues. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixture of Gd(3+) and Yb(3+)/Nd(3+) complexes using an identical chelator. Given the presence of two inner sphere water molecules, important for MRI applications of the corresponding Gd(3+) analogues, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln(3+) ions but also for the design of combined NIR optical and MRI probes.
Lanthanide(III) Complexes That Contain a Self-Immolative Arm : Potential Enzyme Responsive Contrast Agents for Magnetic Resonance ImagingChemistry - a european journal 18 (5) 1408-1418
Enzyme-responsive MRI-contrast agents containing a "self-immolative" benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the Ln(III) complex, with a concomitant response in its MRI-contrast-enhancing properties. We synthesized and investigated a series of Gd(3+) and Yb(3+) complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for β-galactosidase ; we synthesized complex LnL(1) , its NH(2) amine derivatives formed after enzymatic cleavage, LnL(2) , and two model compounds, LnL(3) and LnL(4) . All of the Gd(3+) complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mM(-1) s(-1) for complexes GdL(1) and GdL(2) , respectively ; 37 °C, 60 MHz), which prevents application of this system as an enzyme-responsive T(1) relaxation agent. Variable-temperature (17) O NMR spectroscopy and (1) H NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd(3+) complexes, including the water-exchange rate (k(ex) (298) , varies in the range 1.5-3.9×10(6) s(-1) ). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log K(H) =5.12(±0.01) and 5.99(±0.01) for GdL(2) and GdL(3) , respectively). The Yb(3+) analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the Yb(III) complexes decreases with increasing pH value (for YbL(3) , k(ex) =1300 s(-1) at pH 8.4 vs. 6000 s(-1) at pH 6.4), thereby resulting in a diminution of the observed CEST effect.
A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL) =17-19, with a high selectivity for lanthanides over Ca(2+) , Cu(2+) , and Zn(2+) . The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex) (298) =7.7-9.3×10(6) s(-1) ) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV(≠) =7.2-8.8 cm(3) mol(-1) ). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively.
Luminescent lanthanide-binding peptides : sensitising the excited states of Eu(III) and Tb(III) with a 1,8-naphthalimide-based antennaOrganic & Biomolecular Chemistry 10 (1) 126-133
The investigation into the luminescence properties of a lanthanide-binding peptide, derived from the Ca-binding loop of the parvalbumin, and modified by incorporating a 1,8-naphthalimide (Naph) chromophore at the N-terminus is described. Here, the Naph is used as a sensitising antenna, which can be excited at lower energy than classical aromatic amino acids, such as tryptophan (the dodecapeptide of which was also synthesised and studied herein). The syntheses of the Naph antenna, its solid phase incorporation into the dodecapeptide, and the NMR investigation into the formation of the corresponding lanthanide complexes in solution is presented. We also show that this Naph antenna can be successfully employed to sensitize the excited states of both europium and terbium ions, the results of which was used to determined the stability constants of their formation complexes, and we demonstrated that our peptide ’loop’ can selectively bind these lanthanide ions over Ca(II).
Drahos, B., Pniok, M., Havlickova, J., Kotek, J., Cisarova, I., Hermann, P., Lukes, I., Toth, E. (2011)
Mn2+ complexes of 1-oxa-4,7-diazacyclononane based ligands with acetic, phosphonic and phosphinic acid pendant arms : Stability and relaxation studiesDalton Transactions (2011) 40 (39) 10131-10146 - doi : 10.1039/C1DT10543D
A new class of macrocyclic ligands based on 1-oxa-4,7-diazacyclononane was synthesized and their Mn2+ complexes were investigated with respect to stability and relaxation properties. Each ligand has two pendant arms involving carboxylic (H2L1 - 1-oxa-4,7-diazacyclononane-4,7-diacetic acid), phosphonic (H4L2 - 1-oxa-4,7-diazacyclononane-4,7-bis(methylenephosphonic acid)), phosphinic (H2L3 - 1-oxa-4,7-diazacyclononane-4,7-bis(methylenephosphinic acid)) or phenylphosphinic (H2L4 - 1-oxa-4,7-diazacyclononane-4,7-bis[methylene(phenyl)phosphinic acid]) acid moieties. H2L3 and H2L4 were synthesized for the first time. The crystal structure of the Mn2+ complex with H2L4 confirmed a coordination number of 6 for Mn2+. The protonation constants of all ligands and the stability constants of their complexes with Mn2+ and some biologically or biomedically relevant metal ions were determined by potentiometry. The protonation sequence of H2L3 was followed by 1H and 31P NMR titration and the second protonation step was attributed to the second macrocyclic nitrogen atom. The potentiometric data revealed a relatively low thermodynamic stability of the Mn2+ complexes with all ligands investigated. For H2L3 and H2L4, full Mn2+ complexation cannot be achieved even with 100% ligand excess. The transmetallation of MnL1 and MnL2 with Zn2+ was too fast to be followed at pH 6. Variable temperature 1H NMRD and 17O NMR measurements have been performed on MnL1 and MnL2 to provide information on water exchange and rotational dynamics. The 17O chemical shifts indicate hydration equilibrium between mono- and bishydrated species for MnL1, while MnL2 is monohydrated. The water exchange is considerably faster on MnL1 (kex298 = 1.2 [times] 109 s-1) than on MnL2 (kex298 = 1.2 [times] 107 s-1). Small endogenous anions (phosphate, carbonate, citrate) do not replace the coordinated water in either of the complexes, but they induce their slow decomposition. All Mn2+ complexes are stable toward air-oxidation.
Gallium complexes are gaining increasing importance in biomedical imaging thanks to the practical advantages of the (68)Ga isotope in Positron Emission Tomography (PET) applications. (68)Ga has a short half-time (t(1/2) = 68 min) ; thus the (68)Ga complexes have to be prepared in a limited time frame. The acceleration of the formation reaction of gallium complexes with macrocyclic ligands for ; application in PET imaging represents a significant coordination chemistry challenge. Here we report a detailed kinetic study of the formation reaction of the highly stable Ga(NOTA) from the weak citrate complex (H(3)NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid). The transmetalation has been studied using (71)Ga NMR over a large pH range (pH = 2.01-6.00). The formation of Ga(NOTA) is a two-step process. First, a monoprotonated intermediate containing coordinated citrate, GaHNOTA(citrate)*, forms in a rapid equilibrium step. The rate-determining step of the reaction is the deprotonation and slow rearrangement of the intermediate accompanied by the citrate release. The observed reaction rate shows an unusual pH dependency with a minimum at pH 5.17. In contrast to the typical formation reactions of poly(amino carboxylate) complexes, the Ga(NOTA) formation from the weak citrate complex becomes considerably faster with increasing proton concentration below pH 5.17. We explain this unexpected tendency by the role of protons in the decomposition of the GaHNOTA(citrate)* intermediate which proceeds via the protonation of the coordinated citrate ion and its subsequent decoordination to yield the final product Ga(NOTA). The stability constant of this intermediate, log K(GaHNOTA(citrate)*) = 15.6, is remarkably high compared to the corresponding values reported for the formation of macrocyclic lanthanide(III)-poly(amino carboxylates). These kinetic data do not only give mechanistic insight into the formation reaction of Ga(NOTA), but might also contribute to establish optimal experimental conditions for the rapid preparation of Ga(NOTA)-based radiopharmaceuticals for PET applications.
Mn(2+) Complexes with 12-Membered Pyridine Based Macrocycles Bearing Carboxylate or Phosphonate Pendant Arm : Crystallographic, Thermodynamic, Kinetic, Redox, and (1)H/(17)ORelaxation Studies. Inorganic Chemistry 50 (24) 12785-12801
Mn(2+) complexes represent an alternative to Gd(3+) chelates which are widely used contrast agents in magnetic resonance imaging. In this perspective, we investigated the Mn(2+) complexes of two 12-membered, pyridine-containing macrocyclic ligands bearing one pendant arm with a carboxylic acid (HL(1)), 6-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene) or a phosphonic acid function (H(2)L(2), 6-dihydroxyphosphorylmethyl-3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene). Both ligands were synthesized using nosyl or tosyl amino-protecting groups (starting from diethylenetriamine or tosylaziridine). The X-ray crystal structures confirmed a coordination number of 6 for Mn(2+) in their complexes. In aqueous solution, these pentadentate ligands allow one free coordination site for a water molecule. Potentiometric titration data indicated a higher basicity for H(2)L(2) than that for HL(1), related to the electron-donating effect of the negatively charged phosphonate group. According to the protonation sequence determined by (1)H and (31) pH-NMR titrations, the first two protons are attached to macrocyclic amino groups whereas the subsequent protonation steps occur on the pendant arm. Both ligands form thermodynamically stable complexes with Mn(2+), with full complexation at physiological pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn(2+) under various pHs. The dissociation of MnL(2) is instantaneous (at pH 6). For MnL(1)), the dissociation is very fast (k(obs) = 1-12 x 10(3) s(-1)), much faster than that for MnDOTA, MnNOTA, or the Mn(2+) complex of the 15-membered analogue. It proceeds exclusively via the dissociation of the monoprotonated complex, without any influence of Zn(2+). In aqueous solution, both complexes are air-sensitive leading to Mn(3+) species, as evidenced by UV-vis and (1)H NMRD measurements and X-ray crystallography. Cyclic voltammetry gave low oxidation peak potentials (E(ox) = 0.73 V for MnL(1) and E(ox), = 0.68 V for MnL(2)), in accordance with air-oxidation. The parameters governing the relaxivity of the Mn(2+) complexes were determined from variable-temperature (17)O NMR and (1)H NMRD data. The water exchange is extremely fast, k(ex) = 3.03 and 1.77 X 10(9) s(-1) for MnL(1) and MnL(2), respectively. Variable-pressure (17)O NMR measurements have been performed to assess the water exchange mechanism on MnL(1) and MnL(2) as well as on other Mn(2+) complexes. The negative activation volumes for both MnL(1) and MnL(2) complexes confirmed an associative mechanism of the water exchange as expected for a hexacoordinated Mn(2+) ion. The hydration number of q = 1 was confirmed for both complexes by (17)O chemical shifts. A relaxometric titration with phosphate, carbonate or citrate excluded the replacement of the coordinated water molecule by these small endogenous anions.
Influence of Calcium-Induced Aggregation on the Sensitivity of Aminobis(methylenephosphonate)-Containing Potential MRI Contrast Agents.Inorganic Chemistry 50 (14) 6472-6481
A novel class of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenecarboxylic) acid (DO3A)-based lanthanide complexes with relaxometric response to Ca(2+) was synthesized, and their physicochemical properties were investigated. Four macrocyclic ligands containing an alkyl-aminobis(methylenephosphonate) side chain for Ca(2+)-chelation have been studied (alkyl is propyl, butyl, pentyl, and hexyl for L(1), L(2), L(3), and L(4), respectively). Upon addition of Ca(2+), the r(1) relaxivity of their Gd(3+) complexes decreased up to 61% of the initial value for the best compounds GdL(3) and GdL(4). The relaxivity of the complexes was concentration dependent (it decreases with increasing concentration). Diffusion NMR studies on the Y(3+) analogues evidenced the formation of agglomerates at higher concentrations ; the aggregation becomes even more important in the presence of Ca(2+). (31)P NMR experiments on EuL(1) and EuL(4) indicated the coordination of a phosphonate to the Ln(3+) for the ligand with a propyl chain, while phosphonate coordination was not observed for the analogue bearing a hexyl linker. Potentiometric titrations yielded protonation constants of the Gd(3+) complexes log K(H1) values for all comlexes lie between 6.12 and 7.11 whereas log K(H2) values are between 4.61 and 5.87. Luminescence emission spectra recorded on the Eu(3+) complexes confirmed the coordination of a phosphonate group to the Ln(3+) center in EuL(1). Luminescence lifetime measurements showed that Ca-induced agglomeration reduces the,hydration number which is the main cause for the change in r(1), Variable temperature (17)O NMR experiments evidenced high water exchange rates on GdL(1), GdL(2), and GdL(3) comparable to that of the aqua ion.
Macrocyclic Receptor Showing Extremely High Sr(II)/Ca(II) and Pb(II)/Ca(II) Selectivities with Potential Application in Chelation Treatment of Metal IntoxicationInorganic Chemistry - 50 (8) 3772-3784 Delgado-Pinar, E. Albelda, M. T. Frias, J. C. Barreiro, O. Tejera, E. Kubicek, V. Jimenez-Borreguero, L. J. Sanchez-Madrid, F. Toth, E. Alarcon, J. & Garcia-Espana, E. (2011)
Toth, E. & Petoud, S. (2010)
Molecular Recognition of sialic Acid by Lanthanide (III) Complexes through Cooperative Two-site binding.Inorg. Chem. 49, 4212-4223 Henig, J., Tóth, E., Engelmann, J., Gottschalk, S. & Mayer, H.A. (2010)
Macrocyclic Gd3+ Chelates Attached to a Silsesquioxane Core as Potential MRI Contrast Agents - Synthesis, Physicochemical Characterization and Stability Studies.Inorg. Chem. 49, 6124-6138 Garcia, R., Kubícek, V., Drahoš, B., Gano, L., Santos, I.C., Campello, P., Paulo, A., Tóth, E. & Santos, I. (2010)
Synthesis, Characterization and Biological Evaluation of In(III) Complexes Anchored by DOTA-like Chelators Bearing a Quinazoline Moiety.Metallomics 2, 571-580 Campello, M.P., Lacerda, S., Santos, A.C., Pereira, G.A., Geraldes, C.F., Kotek, J., Hermann, P., Vanek, J., Lubal, P., Toth, E. & Santos, I. (2010)
Lanthanide (III) Complexes of 4,10-Bis (phosphonomethyl)-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (trans-H6do2a2p) in Solution and in the Solid State : Structural Studies Along the Series.Chem. Eur. J. 16, 8446-8465 Bonnet, C.S. & Toth, E. (2010)
Towards highly efficient, intelligent and bimodal imaging probes : novel approaches provided by lanthanide coordination chemistry.C. R. Chimie 13, 700-714 Schuhle, D.T., Polasek, M., Lukes, I., Chauvin, T., Toth, E., Schatz, J., Hanefeld, U., Stuart, M.C.A. & Peters, J.A. (2010)
Densely packed Gd(III)-chelates with fast water exchange on a calixarene scaffold : a potential MRI contrast agent.Dalton Trans. 39, 185-191. Drahos, B., Kotek, J., Hermann, P., Lukes, I. & Toth, E. (2010)
Mn2+ Complexes with Pyridine-Containing 15-Membered Macrocycles : Thermodynamic, Kinetic, Crystallographic, and H-1/O-17 Relaxation Studies.Inorg. Chem. 49, 3224-3238. Bonnet, C.S. & Toth, E. (2010)
Hydrophobic chromophore cargo in micellar structures : a different strategy to sensitize lanthanide cations.Chem. Commun. 46, 124-126.
Kubíček, V. & Tóth, E. (2009)
Stability, Water Exchange, and Anion Binding Studies on Lanthanide(III) Complexes with a Macrocyclic Ligand Based on 1,7-Diaza-12-crown-4 : Extremely Fast Water Exchange on the Gd3+ Complex.Inorg. Chem. 48, 8878-8889. Lacerda, S., Campello, M.P., Marques, F., Gano, L., Kubicek, V., Fouskova, P., Toth, E. & Santos, I. (2009)
A novel tetraazamacrocycle bearing a thiol pendant arm for labeling biomolecules with radiolanthanides.Dalton Trans. 23, 4509-4518. Kubicek, V., Hamplova, A., Maribe, L., Mameri, S., Ziessel, R., Toth, E. & Charbonniere, L. (2009)
Relaxation and luminescence studies on hydrated bipyridyl- and terpyridyl-based lanthanide complexes.Dalton Trans. 43, 9466-9474. Garcia, R., Fouskova, P., Gano, L., Paulo, A., Campello, P., Toth, E. & Santos, I. (2009)
A quinazoline-derivative DOTA-type gallium(III) complex for targeting epidermal growth factor receptors : synthesis, characterisation and biological studies.J. Biol. Inorg. Chem. 14, 261-271. Ferreira, M.F., Martins, A.F., Martins, J.A., Ferreira, P.M., Toth, E. & Geraldes, C. (2009)
Gd(DO3A-N-alpha-aminopropionate) : a versatile and easily available synthon with optimized water exchange for the synthesis of high relaxivity, targeted MRI contrast agents.Chem. Commun. 42, 6475-6477.
Pellegatti, L., Zhang, J., Drahos, B, Suzenet, F., Petoud, S. & Tóth, E. (2008)
Lanthanide Complexes Operating as Bimodal Near Infrared Fluorescent Reporters and MRI Contrast AgentsChem. Commun. 6591-6593. Torres, S., Prata, M.I.M., Santos, A.C., Andre, J.P., Martins, J.A., Helm, L., Toth, E., Garcia-Martin, M.L., Rodrigues, T.B., Lopez-Larrubia, P., Cerdan, S. & Geraldes, C. (2008)
Gd(III)-EPTPAC(16), a new self-assembling potential liver MRI contrast agent : in vitro characterization and in vivo animal imaging studies.NMR Biomed. 21, 322-336. Pellegatti, L., Zhang, J., Drahos, B., Villette, S., Suzenet, F., Guillaumet, G., Petoud, S. & Toth, E. (2008)
Pyridine-based lanthanide complexes : towards bimodal agents operating as near infrared luminescent and MRI reporters.Chem. Commun. 48, 6591-6593. Mato-Iglesias, M., Roca-Sabio, A., Palinkas, Z., Esteban-Gomez, D., Platas-Iglesias, C., Toth, E., de Blas, A. & Rodriguez-Blas, T. (2008)
Lanthanide complexes based on a 1,7-diaza-12-crown-4 platform containing picolinate pendants : A new structural entry for the design of magnetic resonance imaging contrast agents.Inorg. Chem. 47, 7840-7851. Chauvin, T ; Durand, P ; Bernier, M ; Meudal, H ; Doan, BT ; Noury, F ; Badet, B ; Beloeil, JC ; Tóth, E (2008)
Detection of enzymatic activity by PARACEST MRI : a general approach to target a large variety of enzymesAngew. Chem. Int. Edit. 47 (23) 4370 -4372 Dhingra, K ; Fousková, P ; Angelovski, G ; Maier, ME ; Logothetis, NK ; Tóth, E (2008)
Towards extracellular Ca2+ sensing by MRI : synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexesJournal of Biological Inorganic Chemistry 13 (1) 35-46
Two new bismacrocyclic Gd3+ chelates containing a specific Ca2+ binding site were synthesized as potential MRI contrast agents for the detection of Ca2+ concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca(2+)sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L-1) or by a propylene (L-2) unit [H(4)BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid ; H(3)DO(3)A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd3+ complexes towards Ca2+ and Mg2+ was studied by H-1 relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca2+ binding to Gd2L1 and Gd(2)L2, respectively, with a distinct selectivity of Gd2L1 towards Ca2+ compared with Mg2+.
In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applicationsContrast Media and Molecular Imaging 3 (2) 78-85
Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N’’,N’’-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.
Facile Synthesis and Relaxation Properties of Novel Bis-polyazamacrocyclic Gd3+ Complexes : an Attempt towards Calcium Sensitive MRI Contrast AgentsInorganic Chemistry 47 1370-1381 Livramento, JB ; Helm, L ; Sour, A ; O’Neil, C ; Merbach, AE ; Tóth, E (2008)
A benzene-core trinuclear GdIII complex : towards the optimization of relaxivity for MRI contrast agent applications at high magnetic fieldDalton Transactions (9) 1195-1202
A novel ligand, H(12)L, based on a trimethylbenzene core bearing three methylenediethylenetriamine-N,N,N’’,N’’-tetraacetate moieties (-CH(2)DTTA(4-)) for Gd(3+) chelation has been synthesized, and its trinuclear Gd(3+) complex [Gd(3)L(H(2)O)(6)](3-) investigated with respect to MRI contrast agent applications. A multiple-field, variable-temperature (17)O NMR and proton relaxivity study on [Gd(3)L(H(2)O)(6)](3-) yielded the parameters characterizing water exchange and rotational dynamics. On the basis of the (17)O chemical shifts, bishydration of Gd(3+) could be evidenced. The water exchange rate, k(ex)(298) = 9.0 +/- 3.0 s(-1) is around twice as high as k(ex)(298) of the commercial [Gd(DTPA)(H(2)O)](2-) and comparable to those on analogous Gd(3+)-DTTA chelates. Despite the relatively small size of the complex, the rotational dynamics had to be described with the Lipari-Szabo approach, by separating global and local motions.
Noncovalent functionalization of carbon nanotubes with amphiphilic Gd3+ chelates : Toward powerful T-1 and T-2 MRI contrast agentsNano Letters 8 232-236
An amphiphilic gadolinium (III) chelate (GdL) was synthesized from commercially available stearic acid. Aqueous solutions of the complex at different concentrations (from 1 mM to 1 mu M) were prepared and adsorbed on multiwalled carbon nanotubes. The resulting suspensions were stable for several days and have been characterized with regard to magnetic resonance imaging (MRI) contrast agent applications. Longitudinal water proton relaxivities, r(1), have been measured at 20, 300, and 500 MHz. The r(1) values show a strong dependence on the GdL concentration, particularly at low field.
Gd(III)-EPTPAC16, a new self-assembling potential liver MRI contrast agent : in vitro characterization and in vivo animal imaging studiesNMR in Biomedicine 21, 322-336.
The recently reported amphiphilic chelate, [Gd(EPTPAC(16))(H(2)O)](2-), forms supramolecular aggregates in aqueous solution by self-assembly of the monomers with a relaxometrically determined critical micellar concentration (CMC) of 0.34 mM. The effect of sonication on the aggregate size was characterized by dynamic light scattering and relaxometry, indicating the presence of premicellar aggregates and an overall decrease in aggregate size and polydispersity upon sonication, slightly below the CMC. [(153)Sm](EPTPAC(16))(H(2)O)(2-) radiotracer was evaluated in vivo from gamma scintigraphy and biodistribution in Wistar rats.
Laus, S ; Sitharaman, B ; Tóth, E ; Bolskar, RD ; Helm, LM ; Wilson, LJ ; Merbach, AE (2007)
Water-soluble, endohedral gadofullerenes exhibit considerably higher relaxivities than clinically used Gd3+-chelates and are currently explored as potential magnetic resonance imaging (MRI) contrast agents. The relaxivities of Gd@C-60(OH)(x) (x approximate to 27) and Gd@C-60[C(COOHyNa1-y)(2)](10) were previously found to vary with pH because of pH-dependent aggregation. By relaxometric measurements, we proved that aggregation can be suppressed by salt addition (75-100 equiv of sodium phosphate). In the aim of better understanding paramagnetic relaxation mechanisms in water-soluble gadofullerenes, we recorded variable-temperature and multiple-field O-17 and H-1 relaxation rates for Gd@C-60(OH)(x) and Gd@C-60[C(COOHyNa1-y)(2)](10) in both aggregated and disaggregated state (monomers). In the aggregated solutions, the O-17 T-1 and T-2 values are very different.
Monopropionate analogues of DOTA4- and DTPA5- : kinetics of formation and dissociation of their lanthanide(III) complexesDalton Transactions (32) 3572-3581
The replacement of an acetate function of the macrocyclic DOTA(4-) ( DO3A-Nprop(4-)) or the acyclic DTPA(5-) in terminal position ( DTTA- Nprop(5-)) has been recently shown to result in a signifi. cant increase of the water exchange rate on the Gd3+ complexes, which makes these chelates potential contrast agents for MRI applications. Here, two novel and straightforward synthetic routes to H(4)DO3A- Nprop are described. Protonation constants of DO3A- Nprop4- and stability constants with several alkaline earth and transition metal ions have been determined by potentiometry. For each metal, the thermodynamic stability constant is decreased in comparison to the DOTA chelates. The formation reaction of LnDO3A- Nprop(-) complexes ( Ln = Ce, Gd and Yb) proceeds via the rapid formation of a diprotonated intermediate and its subsequent deprotonation and rearrangement in a slow, OH- catalyzed process. The stability of the LnH(2)DO3A- Nprop* intermediates is similar to those reported for the corresponding DOTA analogues.
H5EPTPACH2OH : Synthesis, relaxometric characterization and H-1 NMR studies of the solution dynamics of its Ln(III) complexesEuropean Journal of Inorganic Chemistry (35) 5489-5499
The synthesis and characterization of a new metal chelator, 4-(S)-hydroxymethyl-3,6,10-tri(carboxymethyl)-3,6,10-triaza-dodecanedioic acid (H(5)EPTPACH(2)OH), is reported. Protonation constants for the ligand H(5)EPTPACH(2)OH and for the previously reported H(5)EPTPAC16 have been determined by potentiometry, which reveals that both ligands display slightly higher protonation constants relative to that of the ligand DTPA(5-). The stability constant for the [Gd(EPTPACH(2)OH)(H2O)](2-) complex has also been determined by potentiometry. The obtained value (log K-GdL = 16.7) is two orders of magnitude lower than that for the [Gd(EPTPA)(H2O)](2-) complex, which indicates the destabilizing effect of the pendant hydroxymethyl group at the EPTPA backbone. The microscopic protonation scheme has been deduced from the pH dependence of the H-1 NMR spectra of both H(5)EPTPACH(2)OH and H5EPTPAC16 ligands.
Gadolinium(III) Complexes of Mono- and Diethyl Esters of Monophosphonic Acid Analogue of DOTA as Potential MRI Contrast Agents : Solution Structures and Relaxometric StudiesDalton Transactions (4) 493-501
Two new macrocyclic DOTA-like chelates containing one phosphonate pendant arm were synthesised as potential contrast agents for MRI ( magnetic resonance imaging). The chelates bind to the lanthanide(III) in an octadentate manner, via four nitrogen atoms, three carboxylate and one phosphonate oxygen atoms. Solution structures of [Ln(do3apO(Et2))(H2O)] and [Ln(do3ap(OEt))(H2O)](-) were studied using P-31 and H-1 NMR spectroscopy and SAP (square-antiprismatic)/TSAP ( twisted square-antiprismatic) isomerism was observed. Depending on the nature of the lanthanide( III) ion, the lanthanide( III) complexes of H(4)do3ap(OEt) are present in solution as up to four different diastereoisomers observable with NMR. The TSAP isomer is the most abundant at the beginning of the lanthanide series and, with a decrease of the ionic radius of lanthanide( III) ions, both TSAP and SAP forms were observed.
Dinuclear Complexes Formed with the Triazacyclononane Derivative ENOTA4-. High Pressure 17O NMR evidence of an associative water exchange on [MnII2(ENOTA)(H2O)2].Inorganic Chemistry 46 (1) 238-250
Mn2+ has five unpaired d-electrons, a long electronic relaxation time, and labile water exchange, all of which make it an attractive candidate for contrast agent application in medical magnetic resonance imaging. In the quest for stable and nonlabile Mn2+ complexes, we explored a novel dimeric triazacyclononane-based ligand bearing carboxylate functional groups, H(4)ENOTA. The protonation constants of the ligand and the stability constants of the complexes formed with some endogenously important metals (Ca2+, Cu2+, Zn2+), as well as with Mn2+ and Ce3+, have been assessed by NMR methods, potentiometry, and UV-vis spectrophotometry.
Costa, J ; Balogh, E ; Turcry, V ; Tripier, R ; Le Baccon, M ; Chuburu, F ; Handel, H ; Helm, L ; Tóth, E ; Merbach, AE (2006)
Unexpected aggregation in aqueous solution of neutral, xylene-cored dinuclear GdIII chelates in aqueous solutionChemistry-A European Journal 12 (26) 6841-6851
We have synthesized ditopic ligands L-1, L-2, and L-3 that contain two DO3A(3-) metal-chelating units with a xylene core as a noncoordinating linker (DO3A(3-) = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate ; L-1 = 1,4-bis[4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane-1-yl]methyl-2 benzene ; L-2 = 1,3-bis[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]methylbenzene ; L 3 = 3,5bis[4,7,10-tris(carboxymethyl)-1,4,7,10- tetra azacyclododecane-1-yl]methylbenzoic acid). Aqueous solutions of the dinuclear Gd-III complexes formed with the three ligands have been investigated in a variable-temperature, multiple-field O-17 NMR and H-1 relaxivity study.
Supramolecular assembly of an amphiphilic GdIII chelate : tuning the reorientational correlation time and the water exchange rateChemistry-A European Journal 12 (3) 940-948
We report the synthesis and characterization of the novel ligand H(5)EPTPA-C-16 ((hydroxymethylhexade-canoyl ester) ethylenepropylenetriami-nepentaacetic acid). This ligand was designed to chelate the Gd-III ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (k(ex)) on the Gd-III complex owing to steric compression around the water-binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that form s micelles with a long tumbling time (pi(R)) in aqueous solution. ne critical micelle concentration (cmc = 0.34 mm) of the amphiphilic [Gd(eptpa-C-16)(H2O)](2-) chelate was determined by variable-concentration proton relaxivity measurements.
The heterotritopic ligand [bpy(DTTA)(2)](8-) has two diethylenediamine e-tetra acetate units for selective lanthanide(III) coordination and one bipyridine function for selective Fe-II coordination. In aqueous solution and in the presence of these metals, the ligand is capable of self-assembly to form a rigid supramolecular metallostar structure, Fe[Gd(2)bpy(DTTA)(2)(H(2)0)(4)](3)(4-). We report here the physicochemical characterization of the dinuclear complex [Gd(2)bpy(DTTA)(2)(H2O)(4)](2-) and the metallostar Fe[Gd(2)bpy(DTTA)(2)(H2O)(4)](3)(4-) with regard to potential MRI contrast agent applications. A combination of pH potentiometry and H-1 NMR spectroscopy has been used to determine protonation constants for the ligand [bpy(DTTA)(2)](8-) and for the complexes [Febpy(DTTA)(2)(3)](22-) and [Y(2)bpy(DTTA)(2)](2-). In addition, stability constants have been measured for the dinuclear chelates [M(2)bpy(DTTA)(2)](n-) formed with M = Gd3+ and Zn2+ (logK(GdL) = 18.2 ; logK(ZnL) = 18.0 ; logK(ZnHL) = 3.4).
Pyridine and phosphonate containing acyclic ligands for stable lanthanide complexation. Unprecedently fast water exchange on the GdIII chelatesInorganic Chemistry 45 8719-8728 Mato-Iglesias, M ; Balogh, E ; Platas-Iglesias, C ; Tóth, E ; de Blas, A ; Rodríguez-Blas, T (2006)
Pyridine and phosphonate containing acyclic ligands for stable lanthanide complexation. An experimental and theoretical study to assess solution structure of LnIII complexesDalton Transactions 5404-5415 Burai, L ; Tóth, E ; Bazin, H ; Benmelouka, M ; Jászberényi, Z ; Helm, L ; Merbach, AE (2006)
Phosphinic derivative of DTPA conjugated to a G5 PAMAM dendrimer : an 17O and 1H relaxometric study of its Gd(III) complexDalton Transactions 3399-3406
A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer via a benzylthiourea linkage. The Gd(III) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3+ via three nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere.
First in vivo MRI assessment of a self-assembled metallostar compound endowed with a remarkable high field relaxivityContrast Media & Molecular Imaging 1 (1) 30-40
[Fe[Gd(2)bpy(DTTA)(2)(H2O)(4)](3)}(4-) is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd3+ centres confined into a small molecular space. its proton relaxivity is particularly remarkable at very high magnetic fields (r(1) = 15.8 mM(-1) s(-1) at 200 MHz, 37 degrees C, in H2O). Here we report the first in vivo MRI feasibility study, complemented with dynamic gamma scintigaphic imaging and biodistribution experiments using the Sm-153-enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H2O)](-) = GdDOTA).
Tóth, E ; Bolskar, RD ; Borel, A ; González, G ; Helm, L ; Merbach, AE ; Sitharaman, B ; Wilson, LJ (2005)
The water-soluble endohedral gadofullerene derivatives, Gd@C-60(OH)(x) and Gd@C-60[C(COOH)(2)](10), have been characterized with regard to their MRI contrast agent properties. Water-proton relaxivities have been measured in aqueous solution at variable temperature (278-335 K), and for the first time for gadofullerenes, relaxivities as a function of magnetic field (5 x 10(-4) to 9.4 T ; NMRD profiles) are also reported. Both compounds show relaxivity maxima at high magnetic fields (30-60 MHz) with a maximum relaxivity of 10.4 mM(-1) s(-1) for Gd@C-60[C(COOH)(2)](10) and 38.5 mM(-1) s(-1) for Gd@C-60(OH)(x) at 299 K. Variable-temperature, transverse and longitudinal 170 relaxation rates, and chemical shifts have been measured at three magnetic fields (B = 1.41, 4.7, and 9.4 T), and the results point exclusively to an outer sphere relaxation mechanism.
The complex [Gd(L)(H2O)](3-) (H6L = N,N-’-bis(6-carboxy-2-pyridylmethyl) ethylenediamine-N,N’-methylenephosphonic acid) displays the highest water exchange rate ever measured for a Gd(III) chelate (k(ex)(298) = 8.8 x 10(8) s(-1)), which is attributed to the flexibility of the metal coordination environment.
Synthesis and complexation properties of DTPA-N,N,N’’,N’’-bis[bis(butyl)]-N’-methyl-tris(amide). Kinetic stability and water exchange of its Gd3+ complexDalton Transactions 694-701.
A novel DTPA-tris(amide) derivative ligand, DTPA-N,N"-bis [bis(n-butyl)] -N-methyl-tris(amide) (H2L3) was synthesized. With Gd3+, it forms a positively charged [Gd(L-3)](+) complex, whereas with Cu2+ and Zn2+ [ML3], [MHL3](+) and [M2L3](2+) species are formed. The protonation constants of H2L3 and the stability constants of the complexes were determined by pH potentiometry. The stability constants are lower than those for DTPA-N,N"-bis [bis(n-butyl) amide)] (H3L2), due to the lower negative charge and reduced basicity of the amine nitrogens in (L-3)(2-). The kinetic stability of [Gd(L-3)](+) was characterised by the rates of metal exchange reactions with Eu3+, Cu2+ and Zn2+. The exchange reactions, which occur via proton and metal ion assisted dissociation of [Gd(L-3)](+), are significantly slower than for [Gd(DTPA)](2-), since the amide groups cannot be protonated and interact only weakly with the attacking metal ions.
We report the nanoscale loading and confinement of aquated Gd3+ (n)-ion clusters within ultra-short single-walled carbon nanotubes (US-tubes) ; these Gd3+ (n)@US-tube species are linear superparamagnetic molecular magnets with Magnetic Resonance Imaging (MRI) efficacies 40 to 90 times larger than any Gd3+-based contrast agent (CA) in current clinical use.
Separation and characterization of the two diastereomers for [Gd(DTPA-bz-NH2)(H2O)]2-, a common synthon in macromolecular MRI contrast agents. Their water exchange and isomerization kineticsInorganic Chemistry 44 (10) 3561-3568
Chiral, bifunctional poly(amino carboxylate) ligands are commonly used for the synthesis of macromolecular, Gd-III-based MRI contrast agents, prepared in the objective of increasing relaxivity or delivering the paramagnetic Gd-III to a specific site (targeting). Complex formation with such ligands results in two diastereomeric forms for the complex which can be separated by HPLC. We demonstrated that the diastereomer ratio for Ln(III) DTPA derivatives (&SIM; 60:40) remains constant throughout the lanthanide series, in contrast to Ln(III) EPTPA derivatives, where it varies as a function of the cation size with a maximum for the middle lanthanides (DTPA(5-) = diethylenetriaminepentaacetate ; EPTPA(5-) = ethylenepropylenetriaminepentaacetate).
Rotational Dynamics Account for pH-Dependent Relaxivities of PAMAM Dendrimeric, Gd-based Potential MRI Contrast AgentsChemistry, A European Journal 11 3064-3076
The EPTPA(5-) chelate, which ensures fast water exchange in Gd-III complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H(5)EPTPA = ethylenepropylenetriamine-N,N,N’,N",N"-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)(111) G7-(GdEPTPA)(253) and G9-(GdEPTPA)(1157) decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r(1) = 20.5, 28.3 and 27.9 mm(-1)s(-1), respectively, at 37 degrees C, 30 MHz).
Lanthanide(III) chelates of DTPA-bisamide glycoconjugates : potential imaging agents targeted for the asyaloglycoprotein receptorEuropean Journal of Inorganic Chemistry 2110-2119 Balogh, E ; Tripier, R ; Ruloff, R ; Tóth, E (2005)
Kinetics of formation and dissociation of lanthanide(III) complexes with the 13-membered macrocyclic ligand TRITA4-Dalton Transactions 1058-1065
The tetraazamacrocyclic ligand TRITA(4-) is intermediate in size between the widely studied and medically used 12-membered DOTA(4-) and the 14-membered TETA(4-). The kinetic inertness of GdTRITA was characterized by the rates of exchange reactions with Zn2+ and Eu3+. In the Zn2+ exchange, a second order [H+] dependence was found for the pseudo-first-order rate constant (k(0) = (4.2 +/- 0.5) x 10(-7) s(-1) ; k’ = (3.5 +/- 0.3) x 10(-1) M-1 s(-1), k" = (1.4 +/- 0.4) x 10(3) M-2 s(-1)). In the Eu3+ exchange, at pH
High Relaxivity Confined to a Small Molecular Space : A Metallostar-based, Potential MRI Contrast AgentAngewandte Chemie, International Edition 44 1504-1508 Jászberényi, Z ; Sour, A, ; Tóth, E ; Benmelouka, M ; Merbach, AE (2005)
Dinuclear, bishydrated GdIII polyaminocarboxylates with a rigid xylene core display remarkable proton relaxivitiesInorganic Chemistry 44 4747-4755 Laus, S ; Sitharaman, B ; Tóth, E ; Bolskar, RD ; Helm, L ; Asokan, S ; Wong, MS ; Wilson, LJ ; Merbach, AE (2005)
Destroying Gadofullerene Aggregates by Salt Addition in Aqueous Solution of Gd@C60(OH)x and Gd@C60[C(COOH)2]10Journal of The American Chemical Society 127 9368-9369
Tóth, E ; Helm, L ; Merbach, AE (2004)
Lanthanide(III) Complexes of DOTA-Glycoconjugates : a Potential New Class of Lectin-Mediated Medical Imaging AgentChemistry-A European Journal, 10 (22) 5804-5816
The synthesis and characterization of a new class of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) monoamide-linked glycoconjugates (glucose, lactose and galactose) of different valencies (mono, di and tetra) and their Sm-III, Eu-III and Gd-III complexes are reported. The H-1 NMR spectrum of Eu-III-DOTALac(2) shows the predominance of a single structural isomer of square antiprismatic geometry of the DOTA chelating moiety and fast rotation about the amide bond connected to the targeting glycodendrimer. The in vitro relaxivity of the Gd-III-glycoconjugates was studied by H-1 nuclear magnetic relaxation dispersion (NMRD), yielding parameters close to those reported for other DOTA monoamides. The known recognition of sugars by lectins makes these glycoconjugates good candidates for medical imaging agents (MRI and gamma scintigraphy).
MRI contrast properties of self-aggregated nanoparticles made from Gd-III and 1,2,4,5-tetrakis(pyrazol-1-yl-methyl-3-carboxylate)benzene (L) are investigated. Viscosity of GdL2 suspensions and size-characteristics of GdL2 nanoparticles allow an estimate of their large rotational correlation time. Moreover, two to three H2O molecules are bound, on average, to Gd-III ions, as deduced from O-17 NMR titration of the Dy-III analogue. The large relaxivity of the particles, along with the prominent peak in the range 20-60 MHz, are the consequence of these two properties. Longitudinal (r(1)) and transverse (r(2)) relaxivities are determined as a function of monomer concentration at 20degreesC and 20 MHz. The ratio r(1)/r(2) appears to be favorable for MR imaging using T-1-weighted gradient echo sequences. According to preliminary tests conducted under physiological conditions, the GdL2 nanoparticles have some potential as contrast agent provided their stability can be increased. (C) 2003 Elsevier B.V. All rights reserved.
Platas-Iglesias, C ; Corsi, DM ; Vander Elst, L ; Muller, RN ; Imbert, D ; Bunzli, JCG ; Toth, E ; Maschmeyer, T ; Peters, JA (2003)
Stability, Structure and Dynamics of Cationic Lanthanide(III) Complexes of N,N´-Bis(propylamide)ethylenediamine-N,N´-diacetic acidDalton Transactions (4) 727-737
The cationic [Ln(EDTA-PA(2))](+) complexes (EDTA-PA(2) = EDTA-bispropylamide) have been characterised by a multinuclear NMR study. Y-89 and C-13 NMR data indicate the formation of 1 : 1 and 1 : 2 (Ln : ligand) complexes in aqueous solution. The stability constants of these complexes, as determined by potentiometric measurements, are log K-GdL = 10.3 and log K-GdL2 = 14.3. C-13 Relaxation times of the Nd3+ complex show hexadentate binding of the organic ligand via the two amines, the two carboxylates and the two amide oxygen atoms. The complexes are present in solution as a mixture of three isomers : two trans forms and a cis one.
Novel macrocyclic EuII complexes : fast water exchange related to an extreme metal-coordinated water oxygen distanceChemistry, A European Journal 9 1394-1404 Helm, L ; Toth, E ; Merbach, AE (2003)
Lanthanide ions as magnetic resonance imaging agents. Nuclear and electronic relaxation properties. Applications.Metal Ions in Biological Systems, Sigel, S ; Sigel, Vol. H 40 589-642 - Editor(s) : Eds. Marcel Dekker Inc. New York Burai, L ; Toth, E ; Merbach, AE (2003)
HPLC Separation of Diastereomers of LnIII-Poly(Amino Carboxylates). Direct Assessment of their Water Exchange RateChemical Communications (21) 2680-2681
The diastereomers of two Ln(III)-EPTPA derivatives have been separated by reversed-phase HPLC, and the water exchange rate on their Gd-III complexes has been directly determined by O-17 NMR (H(5)EPTPA = ethylenepropylene-triamine-pentaacetic acid).
GdIII complexes with fast water exchange and high thermodynamic stability : potential building blocks for high relaxivity MRI contrast agentsChemistry-A European Journal 9 (15) 3555-3566
On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd-III poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-)ligand (DTPA = (diethylenetriamine-N,N,N’,N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO25-) to allow for coupling of the chelate to macromolecules.
Nicolle, GM ; Toth, E ; Schmitt-Willich, H ; Raduchel, B ; Merbach, AE (2002)
Variable-temperature, multiple magnetic field O-17 NMR, EPR and variable-temperature H-1 nuclear magnetic relaxation dispersion (NMRD) measurement techniques have been applied to Gadomer 17, a new dendritic contrast agent for magnetic resonance imaging. The macromolecule bears 24 Gd(dota)-monoamide chelates (dota = N,N’,N",N"’,-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) attached to a lysine-based dendrimer. 170 NMR and H-1 NMRD data were analysed simultaneously by incorporating the Lipari-Szabo approach for the description of rotational dynamics. The water exchange rate k(ex)(298) was found to be (1.0 +/- 0. 1) x 10(6) s(-1), a value similar to ex those measured for other Gd(dota) monoamide complexes, and the activation parameters DeltaH = 24.7 +/- 1.3 kJ mol(-1) and DeltaS* = -47.4 +/- 0.2 JK(1) mol(-1).
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O-17 NMR and H-1 NMRD studies have been performed on a series of Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives as potential liver-specific magnetic resonance imaging (MRI) contrast agents. They bear aliphatic side chains which make them capable of micellar self-organization. The compounds differ in the length (C10-C18) and in the chemical nature (alkyl or monoamide-alkyl) of their lipophilic chain. We have established a convenient method to determine the critical micellar concentration (cmc) of paramagnetic surfactants by H-1 relaxivity measurements. This technique can be easily used over a large temperature range ; thus, it can find wide application outside the field of MRI contrast agents. The knowledge of the cmc allowed us to determine the parameters governing the water proton relaxivity of the Gd(III) chelates in both nonaggregated and aggregated micellar forms. The relaxation data of the micellar complexes have been interpreted with the Lipari-Szabo approach.
Eu-II-cryptate with optimal water exchange and electronic relaxation : a synthon for potential pO(2) responsive macromolecular MRI contrast agentsChemical Communications (20) 2366-2367
The cryptate [Eu-II (2.2.2)(H2O)(2)](2+) displays several interesting features with respect to pO(2) responsive MRI contrast agent applications : it is relatively stable against oxidation, it has two inner sphere water molecules, and the water exchange and electron spin relaxation rates are in the optimal range to attain high proton relaxivities, provided the rotation is also optimized.
The water exchange process was accelerated for nine-coordinate, monohydrated macrocyclic Gd-III complexes by inducing steric compression around the water binding site ; the increased steric crowding was achieved by replacing an ethylene bridge of DOTA(4-) by a propylene bridge ;double dagger in addition to the optimal water exchange rate, the stability of [Gd(TRITA)(H2O)](-) is sufficiently high to ensure safe medical use which makes it a potential synthon for the development of high relaxivity, macromolecular MRI contrast agents.
Toth, T ; Helm, L ; Merbach, AE (2001)
Similarities and differences between the isoelectronic Gd-III and Eu-II complexes with regard to MRI contrast agent applicationsCoordination Chemistry Reviews 216 363-382
In solution, the [Eu-11(DTPA)(H2O)](3-). [Eu-11(DOTA)(H2O)](2-). [Eu-11(ODDM)(2-) and [Eu-11(ODDA)(H2O)] complexes are less stable towards oxidation than [Eu(H2O)(8)](2+), as shown by their redox potentials (E-1/2 = - 1.35, - 1.18, - 0.92, - 0.82 and - 0.63 V versus Ag / AgC1 electrode, respectively) (DTPA(5) = diethylenetriamine-N,N,N ’ ,N " ,N " -pentaacetate, DOTA(4) = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tertraacetate, ODDM2 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diacetate). In the solid state, the [Eu-11(DTPA)(H2O)](3-) complex is nine-coordinate with one inner-sphere water molecule.
Lipari-Szabo approach as a tool for the analysis of macromolecular gadolinium(III)-based MRI contrast agents illustrated by the [Gd(EGTA-BA-(CH2)(12))](n)(n+) polymerJournal of Biological Inorganic Chemistry 6 (3) 247-255
The parameters governing the water proton relaxivity of the [Gd(EGTA-BA-(CH2)(12))](n)(n+) polymeric complex were determined through global analysis of O-17 NMR, EPR and nuclear magnetic relaxation dispersion (NMRD) data [EGTA-BA(2-)=3,12-bis(carbamoylmethyl)-6,9-dioxa-3,12-diazatetradecanedioate(2-)]. The Lipari-Szabo approach that distinguishes the global motion of the polymer (tau (g)) from the local motion of the Gd(III)-water vector (tau (1)) was necessary to describe the H-1 and O-17 longitudinal relaxation rates : therefore for the first time it was included in the global simultaneous analysis of the EPR,O-17 NMR and NMRD data. The polymer consists on average of only five monomeric units, which limits the intramolecular hydrophobic interactions operating between the (CH,),, groups. Hence the global rotational correlation time is not very high (tau (298)(g)=3880+/-750ps) compared to the corresponding DTPA-BA-based polymer (about 15 monomeric units), where tau (298)(g)=6500 ps. AS a consequence, the relaxivity is limited by the rotation, which precludes the advantage obtained from the fast exchanging chelating unit (k(ex)(298)=2.2+/-0.1x10(6) s(-1)).
We determined the structure of the hydrated Cu(II) complex by both neutron diffraction and first-principles molecular dynamics, In contrast with the generally accepted picture, which assumes an octahedrally solvated Cu(II) ion, our experimental and theoretical results favor fivefold coordination. The simulation reveals that the solvated complex undergoes frequent transformations between square pyramidal and trigonal bipyramidal configurations. We argue that this picture is also consistent with experimental data obtained previously by visible near-infrared absorption, x-ray absorption near-edge structure, and nuclear magnetic resonance methods. The preference of the Cu(II) ion for fivefold instead of sixfold coordination, which occurs for other cations of comparable charge and size, results from a Jahn-Teller destabilization of the octahedral complex.
Seibig, S ; Tóth, E ; Merbach, AE (2000)
Unexpected Difference in the Dynamics and in the Nuclear and Electronic Relaxation Properties of the Isoelectronic [EuII(DTPA)]3- and [GdIII(DTPA)]2- ComplexesJournal of The American Chemical Society 122 (44) 5822-5830 Yerly, F ; Dunand, FA ; Toth, E ; Figueirinha, A ; Kovacs, Z ; Sherry, AD ; Geraldes, CFGC ; Merbach, AE (2000)
Spectroscopic study of the hydration equilibria and water exchange dynamics of lanthanide(III) complexes of 1,7-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO2A)European Journal of Inorganic Chemistry (5) 1001-1006
The hydration state of a series of [Ln(DO2A)(H2O)(n)](+) complexes in aqueous solution at pH = 6.4-7.0 was studied by measuring the lanthanide-induced O-17 shifts (LIS) of water [Ln includes elements from Ce to Yb ; DO2A = 1,7-bis(carboxymethyl)-1,4,7, 10-tetraazacyclododecane]. Their contact contribution, obtained from Reilley plots, indicated a decrease in the inner-sphere water coordination number of the [Ln(DO2A)(H2O)(n)]+ complexes from n = 3 (Ce-Eu), to n = 2 (Tb-Yb). A temperature-dependent UV/Vis absorption study of the 578-582 nm F-7(0) —> D-5(0) transition band of [Eu(DO2A)(H2O)(n)](+) in aqueous solution showed that this complex is present in an equilibrium between eight- and nine-coordinate species with n = 2 and n = 3, respectively.
Mono- and bimetallic lanthanide(III) phenolic cryptates obtained by template reaction : solid state structure, photophysical properties and relaxivityJournal of The Chemical Society-Dalton Transactions (4) 611-618
We report here a structural and photophysical study of lanthanide monometallic complexes with the macrobicyclic axial phenolic cryptand N[(CH2)(2)N=CH-R-CH=N(CH2)(2)](3)N (R=m-C6H2OH-2-Me-5) L as well as of bimetallic complexes with its de-protonated form (L-3H)(3-). The X-ray crystal structure of [DyL(NO3)](NO3)(2). 2CH(3)CN . 0.5H(2)O shows the metal ion being asymmetrically positioned into the macrobicyclic cavity and bonded to seven donor atoms of L and two oxygen atoms of a bidentate nitrate ion. The X-ray crystal structure of the bimetallic cryptate, [Dy-2(L-3H)(NO3)(2)](NO3). 3H(2)O . MeOH, confirms that both Dy(III) ions are held into the cavity of the cryptand at a very short distance from each other, 3.4840(4) Angstrom.
Lanthanide podates with programmed intermolecular interactions : Luminescence enhancement through association with cyclodextrins and unusually large relaxivity of the gadolinium self-aggregatesJournal of The American Chemical Society 122 (44) 10810-10820
The synthesis of the phenyl anchored podand H4L1 fitted with four 3-carboxylate pyrazole arms and programmed for intermolecular interactions is reported, and its protonation constants are determined. interaction with Ln(3+) ions (Ln = La, Eu, Lu) in dilute aqueous solutions leads to complexes with 1:I and 1:2 metal-ligand stoichiometry. The stability constants are in the range log beta (110) = 12.7-13.5 and log beta (120) = 22.5-23.8 (pLn values in the range 9-10). The podates display a fair sensitization of the metal-centered luminescence with an absolute quantum yield of 5% in case of Tb-III. The average numbers of water molecules coordinated to the Ln(III) ion amount to 3.8 and 4.9 for the 1:1 Eu and Tb podates, respectively, as determined by lifetime measurements.
High-pressure NMR kinetics, part 95 - Solution and solid-state characterization of Eu-II chelates : A possible route towards redox responsive MRI contrast agentsChemistry-A European Journal 6 (20) 3761-3770
We report the first solid state X-ray crystal structure for a Eu-II chelate, [C(NH2)(3)](3)[Eu-II(DTPA)(H2O)]. 8H(2)O, in comparison with those for the corresponding Sr analogue, [C(NH2)(3)](3)[Sr(DTPA)(H2O)]. 8H(2)O and for [Sr(ODDA)]. 8H(2)O (DTPA(5-) = diethylenetriamine-N,N,N’,N " ,N " -pentaacetate, ODDA(2-) = 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diacetate). The two DTPA complexes are isostructural due to the similar ionic size and charge of Sr2+ and Eu2+. The redox stability of [Eu-II(ODDA)(H2O)] and [Eu-II(ODDM)](2-) complexes has been investigated by cyclovoltammetry and UV/Vis spectrophotometry (ODDM4- = 1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane-7,16-dimalonate).
The kinetics of the formation reactions between the lanthanide(III) ions Ce3+, Eu3+ and Yb3+ and four cyclen derivative ligands, DO3A-B, DO3A-ME, DO2A and DO2A-2B, were studied by spectrophotometry and a stopped-flow method at 25 degrees C in 1.0 M KCl solutions. The reactions were found to be of first order, which was interpreted in terms of the formation of a diprotonated intermediate, Ln(H2L)(+). The formation of products occurs via deprotonation and rearrangement of the intermediate, characterised by the rate constant, ii,. The rate law obtained, k(r) = k(OH)[OH ], is similar to those obtained for the formation reactions of DOTA and DOTA derivative complexes. The rate constants, k(OH), decrease with decrease in the number of charged carboxylate functional groups in the ligandsl the lowest rates were found for the formation of the DO2A complexes.
We performed variable temperature (0-100 degrees C), concentration and frequency (9.425, 75, 150 and 225 GHz) continuous wave electron paramagnetic resonance (EPR) measurements on three different Gd(III) compounds : [Gd(H2O)(8)](3+), [Gd(DOTA)(H2O)](-) (DOTA : 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) and [Gd(DTPA-BMA)(H2O)] (DTPA-BMA : 1,5-[bis(N-methylcarbamoyl)methyl]-1,3,5-tris(carboxymethyl)-1,5-diamino-3-azapentane) in aqueous solution. A simultaneous analysis of peak-to-peak widths and dynamic frequency shifts provides access to the transverse electronic relaxation, which is described using a transient zero field splitting (ZFS) mechanism with a spin rotation contribution. Our simultaneous analysis procedure involves numerical calculations using the full relaxation matrix and yields results in acceptable agreement with experimental data for reasonable values of the ZFS parameters (trace of the square of the ZFS Hamiltonian Delta(2)=10(19)-10(20) s(-2) depending on the complex, correlation time of the fluctuations tau(v)(298)=10(-11)-10(-10) s). We also discuss the relationship between our approach and recent developments found in the literature.