Discovery of (-)-7-methyl-2-exo-[3′-(6-[¹⁸F]nuoropyridin- 2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (α4β2-nAChR) with optimal positron emission tomography imaging properties

Several isomers of 7-methyl-2-exo-([¹⁸F]fluoropyridinyl- 5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with K_i = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D _7.4 = 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (K_i = 0.3 nM) ((-)-7-methyl-2-exo-[3′-(6-[¹⁸F] fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [ ¹⁸F](-)-6c) and greatest lipophilicity (log D_7.4 = 0.99) exhibited optimal brain kinetics. [¹⁸F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [¹⁸F]-(-)-6c is a potentially superior replacement for 2-[¹⁸F]fluoro-A-85380 and 6-[ ¹⁸F]fluoro-A-85380, the only available nAChR PET radioligands for humans.