Do spiroindolines have the potential to replace vesamicol as lead compound for the development of radioligands targeting the vesicular acetylcholine transporter?. Issue 19 (1st October 2017)

• Record Type: Journal Article
• Authors: Lindemann, Marcel; Deuther-Conrad, Winnie; Moldovan, Rares; Sekhar, Kondapalli Venkata Gowri Chandra; Brust, Peter; Wenzel, Barbara
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 19(2017)
• Page Start: 5107
• Page End: 5113
• Publication Date: 2017-10-01
• Subjects: YBQFMGUWXJJOBE-OWOJBTEDSA-N -- UJLKLUQGBGSJOO-OWOJBTEDSA-N -- DSSGEOKNTGYRDY-OWOJBTEDSA-N -- RDXPBCTWNYFBFI-OWOJBTEDSA-N -- MTENKAMVZFIDIJ-OWOJBTEDSA-N -- WLWBMTWWXNCMJH-OWOJBTEDSA-N; VAChT -- Vesamicol -- Spiroindolines -- PET -- Sigma receptors; 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.2017.03.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 σ1 and σ2 receptors was determined. The compounds possessed VAChT affinities with K i values in the range of 39–376 nM. Binding affinities toward the σ1 and σ2 receptors 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.