Wang Tao, Wang Jingqi, Chen Leyuan, Zhang Xiaojun, Mou Tiantian, An Xiaodan, Zhang Jinming, Zhang Xiaoli, Deuther-Conrad Winnie, Huang Yiyun, Jia Hongmei
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Department of Nuclear Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
J Med Chem. 2023 Sep 28;66(18):12840-12857. doi: 10.1021/acs.jmedchem.3c00735. Epub 2023 Sep 13.
Novel ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore were designed and synthesized for evaluation of their structure-activity relationship to the sigma-2 (σ) receptor and developed as suitable PET radioligands. Compound was found to possess nanomolar affinity ((σ) = 2.57 nM) for the σ receptor, high subtype selectivity (>2000-fold), and high selectivity over 40 other receptors and transporters. Radioligand [F] was prepared with radiochemical yield of 37-54%, > 99% radiochemical purity, and molar activity of 107-189 GBq/μmol. Biodistribution and blocking studies in mice and micro-PET/CT imaging of [F] in rats indicated excellent binding specificity to the σ receptors . Micro-PET/CT imaging of [F] in the U87MG glioma xenograft model demonstrated clear tumor visualization with high tumor uptake and tumor-to-background ratio. Co-injection with CM398 (5 μmol/kg) led to a remarkable reduction of tumor uptake (80%, 60-70 min), indicating high specific binding of [F] in U87MG glioma xenografts.
设计并合成了具有6,7-二甲氧基-1,2,3,4-四氢异喹啉或5,6-二甲氧基异吲哚啉药效基团的新型配体，以评估它们与sigma-2 (σ) 受体的构效关系，并开发成为合适的正电子发射断层显像（PET）放射性配体。发现化合物对σ受体具有纳摩尔亲和力（(σ) = 2.57 nM）、高亚型选择性（>2000倍）以及对40多种其他受体和转运蛋白的高选择性。制备的放射性配体[F]的放射化学产率为37 - 54%，放射化学纯度>99%，摩尔活度为107 - 189 GBq/μmol。在小鼠体内进行的生物分布和阻断研究以及在大鼠体内对[F]进行的微型PET/CT成像表明，其对σ受体具有优异的结合特异性。在U87MG胶质瘤异种移植模型中对[F]进行的微型PET/CT成像显示肿瘤可视化清晰，肿瘤摄取高且肿瘤与背景比值高。与CM398（5 μmol/kg）共同注射导致肿瘤摄取显著降低（80%，60 - 70分钟），表明[F]在U87MG胶质瘤异种移植瘤中具有高特异性结合。
