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 Ki = 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 (Ki = 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 D7.4 = 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.
|Original language||English (US)|
|Number of pages||14|
|Journal||Journal of medicinal chemistry|
|State||Published - Aug 14 2008|
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery