Synthesis and nicotinic acetylcholine receptor binding properties of exo-2-(2'-fluoro-5'-pyridinyl)-7-azabicyclo- [2.2.1]heptane: A new positron emission tomography ligand for nicotinic receptors

Abstract

Epibatidine, a unique alkaloid, was originally isolated from the skin of the Ecuadoran poison frog, Epipedobates tricolor, by Daly and co-workers and has been shown to have the structure exo-2-(2¢-chloro-5¢-pyridinyl)-7-azabicyclo[2.2.1]heptane (1a). Later reports showed that the natural alkaloid possessed the 1R,2R,4S stereochemistry. Numerous biological studies have demonstrated that epibatidine (1a) is a potent analgesic
agent. Its effects appear to be mediated via neuronal nicotinic receptors (nAChRs); however, details of this action at the molecular level have not been fully elucidated. Nevertheless, epibatidine (1a) has been a very useful tool for gaining new information concerning the pharmacological properties of neuronal nAChRs.

Recently, we synthesized and characterized the in vivo binding properties of (+)- and (-)-exo-2-(3-[6-3H]-pyridinyl)-7-azabicyclo[2.2.1]heptane (1c, [3H]norchloroepibatidine, [3H]NCEPB) in rats.5 Both (+)- and (-)-[3H]NCEPB bind with high affinity but with higher levels of specific binding in vivo for nAChR as compared to epibatidine (1a). Other investigators observed similar results with [3H]epibatidine. These studies suggested that exo-2-(2¢-fluoro-5¢-pyridinyl)-7-azabicyclo-[2.2.1]heptane (1b, norchlorofluoroepibatidine, NFEP) might also have favorable binding properties and that the fluorine-18 analog would be useful as a positron
emission tomography (PET) ligand for further characterizationof the nAChRs.