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 p m . Several compounds of this series were radiolabeled with 11 C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [ 11 C]Me‐ p ‐PVC ( K i  =56 p m 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‐[ 18 F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [ 11 C]Me‐ p ‐PVC is more lipophilic. As a result, [ 11 C]Me‐ p ‐PVC accumulated in the brain more rapidly than 2‐[ 18 F]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 [ 11 C]Me‐ p ‐PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo .