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 |
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Authors: | Brown LaVerne Chefer Svetlana Pavlova Olga Vaupel D Bruce Koren Andrei O Kimes Alane S Horti Andrew G Mukhin Alexey G |
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Institution: | Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA. |
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Abstract: | 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. |
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Keywords: | nicotinic acetylcholine receptor positron emission tomography receptor binding |
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