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

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.

Liang, F., Navarro, H., Abraham, P., Kotian, P., Ding, Y. S., Fowler, J., ... Carroll, F. (1997). 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. Journal of Medicinal Chemistry, 40(15), 2293-2295. DOI: 10.1021/jm970187d