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 degrees C to show K(i) values in the range of 9-611 pm. 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 pm at 37 degrees C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the alpha 4 beta 2* 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.
Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
LaVerne
L
Brown
Svetlana
S
Chefer
Olga
O
Pavlova
D Bruce
DB
Vaupel
Andrei O
AO
Koren
Alane S
AS
Kimes
Andrew G
AG
Horti
Alexey G
AG
Mukhin
D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*
C119803:2-fluoro-3-(2-azetidinylmethoxy)pyridine; C449180:5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-pyrrolidinylmethoxy)pyridine; D001384:Azetidines; D002250:Carbon Radioisotopes; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2