18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

• Published in: Bioorganic & medicinal chemistry 2017-07, Vol.25 (14), p.3792-3802
• Main Authors: Wang, Liang, Ye, Jiajun, He, Yingfang, Deuther-Conrad, Winnie, Zhang, Jinming, Zhang, Xiaojun, Cui, Mengchao, Steinbach, Jörg, Huang, Yiyun, Brust, Peter, Jia, Hongmei
• Format: Article
• Language: English
• Subjects: 18F; Brain; Indole-based analogs; Sigma-2 receptors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.05.019

[Display omitted] 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 (Ki=1.79–5.23nM) for σ2 receptors and high subtype selectivity (Ki (σ2)/Ki (σ1)=56–708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [18F]16 and [18F]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.