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Deau E., Robin E., Voinea R., Percina N., Satala G., Finaru A. L., Chartier A., Tamagnan G., Alagille D., Bojarski A. J., Morisset-Lopez S., Suzenet F. and Guillaumet G.

Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by F-18 -PET Imaging in a Primate Brain

Journal of Medicinal Chemistry (2015) 58 (20) 8066-8096 - doi : 10.1021/acs.jmedchem.5b00874

by Frapart - published on , updated on


We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo-[4,5-b]pyridin-2(3H)-ones, irnidazo[4,5-c]pyridin-2(3H)-ones, benzo [d] oxazol-2 (3H) -ones, oxazolo [4,5- b]pyridin-2(3H)-ones and N,N’-dialkylate d benzo [d] imidazol-2 (3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyDpiperidin-1-yOhexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, K-B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, K-B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [F-18] radiolabeled compounds [F-18]79 and [F-18]81 in a primate’s central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.