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

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.