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. 2020 Jul 15;28(14):115560. doi: 10.1016/j.bmc.2020.115560. Epub 2020 May 23.
We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ receptor ligands. All seven ligands exhibited nanomolar affinity for σ receptors (K(σ) = 0.47 - 12.1 nM) and moderate selectivity over σ receptors (K(σ)/ K(σ) = 2 - 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [F]8 was prepared via nucleophilic F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of greater than 99%, and molar activity of 94 - 121 GBq/μmol. Biodistribution studies of [F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% - 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ receptor-rich brain areas. These findings suggest that [F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ receptors.
我们报告了一系列 1-氧杂-8-氮杂螺[4.5]癸烷和 1,5-二氧杂-9-氮杂螺[5.5]十一烷衍生物作为选择性 σ 受体配体的设计、合成和评价。所有七种配体对 σ 受体均表现出纳摩尔亲和力（K(σ) = 0.47-12.1 nM），对 σ 受体具有中等选择性（K(σ)/K(σ) = 2-44）。在这些配体中，化合物 8 表现出最佳的选择性，被选为放射性标记和进一步评价。放射性配体 [F]8 通过相应的 tosylate 前体的亲核 F 取代制备，总分离放射性化学产率为 12-35%，放射性化学纯度大于 99%，摩尔活性为 94-121 GBq/μmol。[F]8 在小鼠中的生物分布研究表明，在 2 分钟时初始脑摄取量高。SA4503 预处理导致脑与血液的比值显著降低（30 分钟时为 70%-75%）。在 ICR 小鼠的离体放射自显影中，放射性示踪剂在 σ 受体丰富的脑区有高积聚。这些发现表明，[F]8 可能是进一步结构修饰的先导化合物，以开发潜在的用于 σ 受体的脑成像剂。
