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. Issue 19 (1st October 2017)

• Record Type: Journal Article
• Authors: Roslin, Sara; De Rosa, Maria; Deuther-Conrad, Winnie; Eriksson, Jonas; Odell, Luke R.; Antoni, Gunnar; Brust, Peter; Larhed, Mats
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 19(2017)
• Page Start: 5095
• Page End: 5106
• Publication Date: 2017-10-01
• Subjects: ACh acetylcholine -- VAChT vesicular acetylcholine transporter -- PET positron emission tomography -- AD Alzheimer's disease -- PD Parkinson's disease -- vesamicol (±)-trans-2-(4-phenylpiperidino)cyclohexanol -- benzovesamicol 3-(4-phenyl-piperidin-1-yl)-1, 2, 3, 4-tetrahydronaphthalen-2-ol -- SAR structure-activity relationship -- [3H]DTG [3H]-1, 3-di-o-tolylguanidine -- Herrmann's palladacycle trans-bis(acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) -- XPhos 2-dicyclo-hexylphosphino-2′, 4′, 6′-triisopropylbiphenyl -- DMAP 4-(dimethylamino)pyridine -- Pd(dba)2 Palladium(dibenzylidene acetone) -- SFC Supercritical fluid chromatography; Vesicular acetylcholine transporter -- VAChT -- PET tracer -- Aminocarbonylation -- 11C-labeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.01.041
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 σ1 and σ2 receptors. 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 [ 11 C]-( ±)-7i shows that (−)-7i can serve as a scaffold for future optimizations to provide improved 11 C-labelled VAChT PET tracers.