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

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• 作者：Emmanuel Deau ; Elodie Robin ; Raluca Voinea ; Nathalie Percina ; Grzegorz Sata艂a ; Adriana-Luminita Finaru ; Agn猫s Chartier ; Gilles Tamagnan ; David Alagille ; Andrzej J. Bojarski ; S茅verine Morisset-Lopez ; Franck Suzenet ; G茅rald Guillaumet
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8066-8096
• 全文大小：1408K
• ISSN：1520-4804

文摘

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, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N鈥?dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT₇R, 5-HT_2AR, 5-HT_1AR, and 5-HT₆R as potent dual 5-HT₇/5-HT_2A serotonin receptors ligands. A thorough study of the structure鈥揳ctivity 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-fluorobenzoyl)piperidin-1-yl)hexyl)-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-HT_2AR. Both antagonists crossed the blood鈥揵rain barrier as evaluated with [¹⁸F] radiolabeled compounds [¹⁸F]79 and [¹⁸F]81 in a primate鈥檚 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-HT_2AR in the CNS.