New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

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

Research output: Contribution to journalArticle

Abstract

A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, Ki = 2310, 1680 pM; (-)-NMI-EPB, Ki = 55, 68 pM). The enantiomers were stereoselectively radiolabeled with 11C. In the distribution studies in the rodent brain [11C](-)-NMI-EPB specifically labeled nAChR whereas [11C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [11C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

Original languageEnglish (US)
Pages (from-to)6168-6170
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number23
DOIs
StatePublished - Dec 1 2008

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Keywords

  • C-11
  • Enantiomers
  • Positron emission tomography (PET)
  • nAChR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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