Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-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.