Evaluation of 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-(S)- pyrrolidinylmethoxy)pyridine and its analogues as PET radioligands for imaging nicotinic acetylcholine receptors

A novel series of compounds derived from the high-affinity nicotinic acetylcholine receptor (nAChR) ligand, 5-(2-(4-pyridinyl)vinyl)-6-chloro-3-((1- methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (Me-p-PVC), originally developed by Abbott Laboratories, was characterized in vitro in nAChR binding assays at 37°C to show K_i values in the range of 9-611 pM. Several compounds of this series were radiolabeled with ¹¹C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [¹¹C]Me-p-PVC (K_i = 56 pM at 37°C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the α4β2* nAChR subtype. Compared with 2-[¹⁸F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [¹¹C]Me-p-PVC is more lipophilic. As a result, [¹¹C]Me-p-PVC accumulated in the brain more rapidly than 2-[¹⁸F]FA. Pharmacological evaluation of Me-p-PVC in mice demonstrated that the toxicity of this compound was comparable with or lower than that of 2-FA. Taken together, these results suggest that [ ¹¹C]Me-p-PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo.