18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain. Issue 14 (15th July 2017)

• Record Type: Journal Article
• Authors: Wang, Liang; Ye, Jiajun; He, Yingfang; Deuther-Conrad, Winnie; Zhang, Jinming; Zhang, Xiaojun; Cui, Mengchao; Steinbach, Jörg; Huang, Yiyun; Brust, Peter; Jia, Hongmei
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 14(2017)
• Page Start: 3792
• Page End: 3802
• Publication Date: 2017-07-15
• Subjects: Sigma-2 receptors -- 18F -- Indole-based analogs -- Brain; 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.2017.05.019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5, 6-dimethoxyisoindoline or 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity ( K i = 1.79–5.23 nM) for σ2 receptors and high subtype selectivity ( K i (σ2 )/ K i (σ1 ) = 56–708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [ 18 F]16 and [ 18 F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10–15% radiochemical yield and radiochemical purity of >99%. Both radiotracers showed high brain uptake and σ2 receptor binding specificity in mice.