Discovery of (-)-7-methyl-2-exo-[3 '-(6-[(18)F]fluoropyridin-2-yl)-5 '-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor ((alpha 4 beta 2-nAChR) with optimal positron emission tomography Imaging properties

作者：Gao Yongjun; Kuwabara Hiroto; Spivak Charles E; Xiao Yingxian; Kellar Kenneth; Ravert Hayden T; Kumar Anil; Alexander Mohab; Hilton John; Wong Dean F; Dannals Robert F; Horti Andrew G^*

来源：Journal of Medicinal Chemistry, 2008, 51(15): 4751-4764.

DOI：10.1021/jm800323d

Several isomers of 7-methyl-2-exo-([(18)F]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 beta-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-[F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D(7.4)=0.99) exhibited optimal brain kinetics. [(18)F](-)-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 alpha 4 beta 2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)-6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

• 出版日期2008-8-14