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

Abstract : 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′-dialkylated 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-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood–brain barrier as evaluated with [18F] radiolabeled compounds [18F]79 and [18F]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.
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https://hal.archives-ouvertes.fr/hal-02068052
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Submitted on : Thursday, March 14, 2019 - 3:29:45 PM
Last modification on : Wednesday, May 15, 2019 - 11:50:05 AM

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Emmanuel Deau, Elodie Robin, Raluca Voinea, Nathalie Percina, Grzegorz Satała, et al.. Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT 7 )/5-Hydroxytryptamine 2A (5-HT 2A ) Receptor Antagonists and Evaluation by [ 18 F]-PET Imaging in a Primate Brain. Journal of Medicinal Chemistry, American Chemical Society, 2015, 58 (20), pp.8066-8096. ⟨10.1021/acs.jmedchem.5b00874⟩. ⟨hal-02068052⟩

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