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

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

Research output: Contribution to journalArticle


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 languageEnglish (US)
Pages (from-to)4751-4764
Number of pages14
JournalJournal of medicinal chemistry
Issue number15
StatePublished - Aug 14 2008


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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