CHARACTERIZATION OF [H-3] ABT-418 - A NOVEL CHOLINERGIC CHANNEL LIGAND

ABT-418 (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent and selective agonist at neuronal nicotinic acetylcholine receptors ( nAChRs) with cognitive enhancing and anxiolytic activities. [H-3]ABT-4 18 was found to bind with high affinity (K-D, = 2.85 +/- 0.14 nM) to m embranes prepared from rat brain. Binding of [H-3]ABT-418 was characte rized by rapid association (T-1/2 = 1.4 +/- 0.3 min) and dissociation (T-1/2 = 2.9 +/- 0.4 min) half-times. The pharmacology of [H-3]ABT-418 binding was consistent with an interaction with the putative alpha 4 beta 2 nAChR subtype. The nAChR agonists, (-)-nicotine, (-)-cytisine a nd (+/-)epibatidine, displayed a high affinity (K-i = 0.8 +/- 0.1, 0.2 +/- 0.1 and 0.05 +/- 0.01 nM, respectively) for [H-3]ABT-418 binding sites, whereas among nAChR antagonists examined, only dihydro-beta-ery throidine competed with high affinity (K-i = 32 +/- 1.5 nM). Although autoradiography studies indicate that the binding distribution of [H-3 ]ABT-418 and (-)-[H-3]cytisine are largely identical, there are some b rain regions including the striatum, olivary pretectal nucleus and the superior colliculus, in which [H-3]ABT-418 demonstrates significantly (P < .05) less binding. The data in the present study demonstrate tha t [H-3]ABT-418 binds with high affinity to a population of binding sit es in the rat brain that have the pharmacological characteristics of n euronal nAChRs, [H-3]ABT-418 may, therefore, serve as a useful radioli gand to further probe the observed differences in pharmacological prop erties between ABT-418 and other nicotinic agonists in vivo.-