Synthesis and in vitro evaluation of 5-substituted benzovesamicol analogs containing N-substituted amides as potential positron emission tomography tracers for the vesicular acetylcholine transporter.

Roslin S, De Rosa M, Deuther-Conrad W, Eriksson J, Odell LR, Antoni G, Brust P, Larhed M

Bioorg. Med. Chem. 25 (19) 5095-5106 [2017-10-01; online 2017-01-25]

Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (±)-7i and (±)-7l had the highest affinities for VAChT. Compound (±)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the σ

Affiliated researcher

PubMed 28185725

DOI 10.1016/j.bmc.2017.01.041

Crossref 10.1016/j.bmc.2017.01.041

pii: S0968-0896(17)30146-3

Publications 9.5.0