Abstract
Reportedly, 2-[18F]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 Ki = 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 (Ki = 28 and 23 pM, respectively) and will be targets for development of 11CH3-labeled derivatives as radiotracers for PET imaging of nAChRs.
Original language | English (US) |
---|---|
Pages (from-to) | 2841-2849 |
Number of pages | 9 |
Journal | Journal of medicinal chemistry |
Volume | 45 |
Issue number | 13 |
DOIs | |
State | Published - Jun 20 2002 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery