Design of $\alpha$7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [$^{18}$F] quinuclidine derivative

Sylvie Mavel (1) , Frédéric Pin (2) , Johnny Vercouillie (3) , Aziz Ouach (4) , Zuhal Gulhan , Gabrielle Chicheri , Christian Jarry (5) , Stéphane Massip (5) , Jean-Bernard Deloye , Denis Guilloteau (3) , Franck Suzenet (2) , Sylvie Chalon (3) , Sylvain Routier (2)

1 Equipe neurogénétique et neurométabolomique
2 ICOA - Institut de Chimie Organique et Analytique
3 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
4 ICOA - Institut de Chimie Organique et Analytique
5 Laboratoire de Pharmacochimie

In this report, we describe the synthesis of a novel library of $\alpha$7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. The potent [$^{18}$F]4 PET tracer was evaluated in rats and its brain accumulation quantified.

Domains: Chemical Sciences; Medicinal Chemistry

Sylvie Mavel, Frédéric Pin, Johnny Vercouillie, Aziz Ouach, Zuhal Gulhan, et al.. Design of $\alpha$7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [$^{18}$F] quinuclidine derivative. European Journal of Medicinal Chemistry, 2014, 82, pp.214 - 224. ⟨10.1016/j.ejmech.2014.04.057⟩. ⟨hal-01826403⟩