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

Publication date: Available online 10 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Liang Wang, Jiajun Ye, Yingfang He, Winnie Deuther-Conrad, Jinming Zhang, Xiaojun Zhang, Mengchao Cui, Jörg Steinbach, Yiyun Huang, Peter Brust, Hongmei Jia
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 = 1.79–5.23 nM) 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.

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