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

Bioorg Med Chem Lett. 2008 Dec 1;18(23):6168-70. doi: 10.1016/j.bmcl.2008.10.012. Epub 2008 Oct 7.

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, K(i)=2310, 1680 pM; (-)-NMI-EPB, K(i)=55, 68 pM). The enantiomers were stereoselectively radiolabeled with (11)C. In the distribution studies in the rodent brain [(11)C](-)-NMI-EPB specifically labeled nAChR whereas [(11)C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [(11)C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Chromatography, High Pressure Liquid
  • Heptanes / chemical synthesis*
  • Heptanes / chemistry
  • Heptanes / pharmacology*
  • Ligands
  • Mice
  • Molecular Structure
  • Papio
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacology*
  • Receptors, Nicotinic / metabolism*
  • Stereoisomerism

Substances

  • 7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo(2.2.1)heptane
  • Bridged Bicyclo Compounds, Heterocyclic
  • Heptanes
  • Ligands
  • Radiopharmaceuticals
  • Receptors, Nicotinic