title: Design of α7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [(18)F] quinuclidine derivative.
abstract: In this report, we describe the synthesis of a novel library of α7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. The potent [(18)F]4 PET tracer was evaluated in rats and its brain accumulation quantified.
authors.affiliation: Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pin
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Johnny
authors.initials: J
authors.lastname: Vercouillie
authors.affiliation: Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ouach
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Zuhal
authors.initials: Z
authors.lastname: Gulhan
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Chicheri
authors.affiliation: Université de Bordeaux, Pharmacochimie, FRE CNRS 3396, 136 Rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jarry
authors.affiliation: Université de Bordeaux, Pharmacochimie, FRE CNRS 3396, 136 Rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Massip
authors.affiliation: Laboratoires Cyclopharma, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Deloye
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.affiliation: Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Suzenet
authors.affiliation: UMR Inserm U930, Université François Rabelais de Tours, CHRU de Tours, Tours, France. Electronic address: sylvie.chalon@univ-tours.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.affiliation: Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France. Electronic address: sylvain.routier@univ-orleans.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005462:Fluorine Radioisotopes; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D011799:Quinazolines; D011812:Quinuclidines; D014326:Tropanes; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Alpha 7nicotinic acetylcholine receptors; In vivo evaluation; Molecular modeling; Quinuclidine; Radiochemistry; SAR; Synthesis; Tropane