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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.

Publication ,  Journal Article
Brown, LL; Kulkarni, S; Pavlova, OA; Koren, AO; Mukhin, AG; Newman, AH; Horti, AG
Published in: J Med Chem
June 20, 2002

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.

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

June 20, 2002

Volume

45

Issue

13

Start / End Page

2841 / 2849

Location

United States

Related Subject Headings

  • Tomography, Emission-Computed
  • Structure-Activity Relationship
  • Receptors, Nicotinic
  • Rats
  • Radioligand Assay
  • Pyrrolidines
  • Pyridines
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
 

Citation

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Brown, L. L., Kulkarni, S., Pavlova, O. A., Koren, A. O., Mukhin, A. G., Newman, A. H., & Horti, A. G. (2002). 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. J Med Chem, 45(13), 2841–2849. https://doi.org/10.1021/jm010550n
Brown, LaVerne L., Santosh Kulkarni, Olga A. Pavlova, Andrei O. Koren, Alexey G. Mukhin, Amy H. Newman, and Andrew G. Horti. “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.J Med Chem 45, no. 13 (June 20, 2002): 2841–49. https://doi.org/10.1021/jm010550n.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

June 20, 2002

Volume

45

Issue

13

Start / End Page

2841 / 2849

Location

United States

Related Subject Headings

  • Tomography, Emission-Computed
  • Structure-Activity Relationship
  • Receptors, Nicotinic
  • Rats
  • Radioligand Assay
  • Pyrrolidines
  • Pyridines
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry