title: New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter - A critical examination of the lead structure.
abstract: To verify vesamicol as lead structure in the development of radioligands for imaging of VAChT in the brain by PET, we systematically modified this molecule and investigated four different groups of derivatives. Structural changes were conducted in all three ring systems A, B, and C resulting in a library of different vesamicol analogs. Based on their in vitro binding affinity toward VAChT as well as σ1 and σ2 receptors, we performed a structure-affinity relationship (SAR) study regarding both affinity and selectivity. The compounds possessed VAChT affinities in the range of 1.32 nM (benzovesamicol) to >10 μM and selectivity factors from 0.1 to 73 regarding σ1 and σ2 receptors, respectively. We could confirm the exceptional position of benzovesamicols as most affine VAChT ligands. However, we also observed that most of the compounds with high VAChT affinity demonstrated considerable affinity in particular to the σ1 receptor. Finally, none of the various vesamicol analogs in all four groups showed an in vitro binding profile suitable for specific VAChT imaging in the brain.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Barthel
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Germany.
authors.forename: Dietlind
authors.initials: D
authors.lastname: Sorger
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schweiger
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Jäckel
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Roghani
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Leipzig, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Schüürmann
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany. Electronic address: b.wenzel@hzdr.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
mesh_terms: D000818:Animals; D001921:Brain; D004305:Dose-Response Relationship, Drug; D005260:Female; D057054:Molecular Imaging; D015394:Molecular Structure; D016716:PC12 Cells; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050494:Vesicular Acetylcholine Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: D010880:Piperidines; D050494:Vesicular Acetylcholine Transport Proteins; C006189:vesamicol
keywords: PET; Sigma receptors; VAChT; Vesamicol