【文章名】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 (a4b2-nAChR) with Optimal Positron Emission Tomography Imaging Properties.
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 (a4b2-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.;
[摘要]：Several isomers of 7-methyl-2-exo-([18F]fluoropyridinyl-5'-pyridinyl)-7-azabicyclo[2.2.1]hept ane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are b-nAChR selective ligands with Ki = 0.02-0.3 nM. The exptl. lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D7.4= 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the ((-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicycl 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. Pharmacol. studies showed that (-)-6c is an a4b2-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.
