title: 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.
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 σ1and σ2receptors. 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 56.7nM 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 improved11C-labelled VAChT PET tracers.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Roslin
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC Box 574, SE-751 23 Uppsala, Sweden. Electronic address: mats.larhed@orgfarm.uu.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D016716:PC12 Cells; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis*
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D008024:Ligands; D010880:Piperidines; D050494:Vesicular Acetylcholine Transport Proteins; C502757:benzovesamicol
keywords: (11)C-labeling; Aminocarbonylation; PET tracer; VAChT; Vesicular acetylcholine transporter