Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2. 1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors

Yongjun Gao, Andrew G. Horti, Hiroto Kuwabara, Hayden T. Ravert, John Hilton, Daniel P. Holt, Anil Kumar, Mohab Alexander, Christopher J. Endres, Dean F. Wong, Robert F. Dannals

Research output: Contribution to journalArticle


A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7- azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3′-(2-[ 18F]-fluoropyridin-5-yl))-5′-pyridinyl]-7-azabicyclo[2.2.1] heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.

Original languageEnglish (US)
Pages (from-to)3814-3824
Number of pages11
JournalJournal of medicinal chemistry
Issue number16
StatePublished - Aug 9 2007


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this