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

Publication date: Available online 25 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sara Roslin, Maria De Rosa, Winnie Deuther-Conrad, Jonas Eriksson, Luke R. Odell, Gunnar Antoni, Peter Brust, Mats Larhed
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 towards the σ1 and σ2 receptor. Enantiomeric resolution gave (+)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (±)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [¹¹C]-(±)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved ¹¹C-labelled VAChT PET tracers.

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