title: Synthesis and evaluation of a novel series of 2-chloro-5-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-3-(2-(4-pyridinyl)vinyl)pyridine analogues as potential positron emission tomography imaging agents for nicotinic acetylcholine receptors.
abstract: Reportedly, 2-[(18)F]fluoro-A-85380, 1, a promising radiotracer for imaging the nicotinic acetylcholine receptor (nAChR) by positron emission tomography (PET) in humans, exhibits slow penetration through the blood-brain barrier (BBB) due to its low lipophilicity. A ligand for nAChRs with greater lipophilicity than that of 1 would be potentially more favorable for PET imaging of nAChR due to its faster penetration through the BBB. Herein, a novel series of compounds has been developed based on the high affinity ligand for nAChRs, 2-chloro-5-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-3-(2-(4-pyridinyl)vinyl)pyridine, 3b. The in vitro binding affinities for the new series were found to be in the range of K(i) = 9-331 pM. A molecular modeling study showed differences in the comformational profiles and the electronic properties of these compounds, which provides further insight into the structure-activity relationships at nAChR. Lipophilicities of the compounds 3b-6b have been found to be substantially higher than that of 1. As a result, compounds 3b-6b might exhibit a faster penetration through the BBB than the less lipophilic 1. The N-methyl derivatives 3b and 6b demonstrated very high affinities at nAChRs (K(i) = 28 and 23 pM, respectively) and will be targets for development of (11)CH(3)-labeled derivatives as radiotracers for PET imaging of nAChRs.
authors.affiliation: Neuroimaging Research Branch and Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: LaVerne L
authors.initials: LL
authors.lastname: Brown
authors.forename: Santosh
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Olga A
authors.initials: OA
authors.lastname: Pavlova
authors.forename: Andrei O
authors.initials: AO
authors.lastname: Koren
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Mukhin
authors.forename: Amy H
authors.initials: AH
authors.lastname: Newman
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed
chemical_list: C459204:2-chloro-5-((1-methyl-2-pyrrolidinyl)methoxy)-3-(2-(4-pyridinyl)ethyl)pyridine; C449180:5-(2-(4-pyridinyl)vinyl)-6-chloro-3-(1-methyl-2-pyrrolidinylmethoxy)pyridine; D008024:Ligands; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic