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

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.