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 - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2015

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

Raluca Voinea
  • Fonction : Auteur
Grzegorz Satała
  • Fonction : Auteur
Adriana-Luminita Finaru
  • Fonction : Auteur
Agnes Chartier
Gilles Tamagnan
  • Fonction : Auteur
Andrzej Bojarski
Séverine Morisset-Lopez
Franck Suzenet
Gérald Guillaumet
  • Fonction : Auteur
  • PersonId : 964449
  • IdRef : 060700777

Résumé

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.

Domaines

Chimie
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Dates et versions

hal-03082898 , version 1 (18-12-2020)

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Citer

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, 2015, 58 (20), pp.8066-8096. ⟨10.1021/acs.jmedchem.5b00874⟩. ⟨hal-03082898⟩
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