title: Do spiroindolines have the potential to replace vesamicol as lead compound for the development of radioligands targeting the vesicular acetylcholine transporter?
abstract: The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron emission tomography (PET). So far the development of VAChT PET radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline based compound class (Sluder et al., 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of N,N-substituted spiro[indoline-3,4'-piperidine] derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward σ1and σ2receptors was determined. The compounds possessed VAChT affinities with Kivalues in the range of 39-376nM. Binding affinities toward the σ1and σ2receptors are in a similar range indicating that the strong structural difference between the spiroindolines and vesamicol did not improve the selectivity. The observed potential to additionally bind to σ receptors let us assume that the herein investigated spiroindolines are not suitable to replace vesamicol as lead compound for the development of VAChT ligands.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Lindemann
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: Rares
authors.initials: R
authors.lastname: Moldovan
authors.affiliation: Department of Chemistry, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, India.
authors.forename: Kondapalli Venkata Gowri Chandra
authors.initials: KVGC
authors.lastname: Sekhar
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; D001923:Brain Chemistry; D005260:Female; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D008099:Liver / Q000737:chemistry; D016716:PC12 Cells; D010880:Piperidines / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry*; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis*
chemical_list: D007211:Indoles; D008024:Ligands; D010880:Piperidines; D011868:Radioisotopes; D013141:Spiro Compounds; D050494:Vesicular Acetylcholine Transport Proteins; C006189:vesamicol; C057812:indoline
keywords: PET; Sigma receptors; Spiroindolines; VAChT; Vesamicol