Wang Liang, Ye Jiajun, He Yingfang, Deuther-Conrad Winnie, Zhang Jinming, Zhang Xiaojun, Cui Mengchao, Steinbach Jörg, Huang Yiyun, Brust Peter, Jia Hongmei
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany.
Bioorg Med Chem. 2017 Jul 15;25(14):3792-3802. doi: 10.1016/j.bmc.2017.05.019. Epub 2017 May 10.
We have designed and synthesized a series of indole-based σ 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=1.79-5.23nM) for σ receptors and high subtype selectivity (K (σ)/K (σ)=56-708). Moreover, they showed high selectivity for σ receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [F]16 and [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 σ receptor binding specificity in mice.
我们设计并合成了一系列以5,6-二甲氧基异吲哚啉或6,7-二甲氧基-1,2,3,4-四氢异喹啉为药效团的基于吲哚的σ受体配体。体外竞争结合试验表明，所有十个配体对σ受体具有低纳摩尔亲和力（K = 1.79 - 5.23 nM）和高亚型选择性（K(σ)/K(σ)= 56 - 708）。此外，它们对σ受体的选择性高于囊泡乙酰胆碱转运体（>1000倍）。通过高效的一锅两步反应序列，使用自制的自动合成模块制备了相应的放射性示踪剂[F]16和[F]21，放射化学产率为10 - 15%，放射化学纯度>99%。两种放射性示踪剂在小鼠体内均表现出高脑摄取和σ受体结合特异性。
