Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [(18)F]-PET Imaging in a Primate Brain.
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 [(18)F] radiolabeled compounds [(18)F]79 and [(18)F]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.
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.
Emmanuel
E
Deau
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS), UPR 4301, Université d'Orléans et INSERM , rue Charles Sadron, 45071 Orléans Cedex 2, France.
Elodie
E
Robin
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.|Centrul de Cercetare 'Chimie Aplicată şi Inginerie de Proces', Universitatea din Bacău , Calea Mărăşesti, nr. 157, 600115 Bacău, Romania.
Raluca
R
Voinea
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.
Nathalie
N
Percina
Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, Kraków 31-343, Poland.
Grzegorz
G
Satała
Centrul de Cercetare 'Chimie Aplicată şi Inginerie de Proces', Universitatea din Bacău , Calea Mărăşesti, nr. 157, 600115 Bacău, Romania.
Adriana-Luminita
AL
Finaru
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.
Agnès
A
Chartier
Molecular NeuroImaging , 60 Temple Street, New Haven, Connecticut 06510, United States.
Gilles
G
Tamagnan
Molecular NeuroImaging , 60 Temple Street, New Haven, Connecticut 06510, United States.
David
D
Alagille
Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, Kraków 31-343, Poland.
Andrzej J
AJ
Bojarski
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS), UPR 4301, Université d'Orléans et INSERM , rue Charles Sadron, 45071 Orléans Cedex 2, France.
Séverine
S
Morisset-Lopez
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.
Franck
F
Suzenet
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, CNRS, UMR 7311 , rue de Chartres, F-45067 Orleans, France.
Gérald
G
Guillaumet
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging*; D015195:Drug Design; D007091:Image Processing, Computer-Assisted; D007553:Isotope Labeling; D008024:Ligands; D008253:Macaca mulatta; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor