Synthesis and evaluation of new 1-oxa-8-azaspiro [4.5]decane derivatives as candidate radioligands for sigma-1 receptors
Synthesis and evaluation of new 1-oxa-8-azaspiro [4.5]decane derivatives as candidate radioligands for sigma-1 receptors
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作为 sigma-1 受体候选放射性配体的新型 1-oxa-8-azaspiro [4.5]decane 衍生物的合成和评价
DOI：
10.1016/j.bmc.2020.115560
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发表时间：
2020
影响因子：
3.5
通讯作者：
Jia Hongmei
中科院分区：
文献类型：
--
作者：
Tian Jiale;He Yingfang;Deuther-Conrad Winnie;Fu Hualong;Xie Fang;Zhang Ying;Wang Tao;Zhang Xiaojun;Zhang Jinming;Brust Peter;Huang Yiyun;Jia Hongmei
我们设计、合成并评价了一系列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 1受体配体。所有7种配体对σ 1受体均表现出纳摩尔亲和力（Ki（σ1）= 0.47 - 12.1 nM），对σ 2受体表现出中等选择性（Ki（σ2）/Ki（σ1）= 2 - 44）。选择在这些配体中具有最佳选择性的化合物8用于放射性标记和进一步评价。放射性配体[18F] 8是通过相应的甲苯磺酸盐前体的亲核18F取代反应制备的，总的分离放化产率为12- 35%，放化纯度大于99%，摩尔活性为94 - 121 GBq/μmol。[18 F] 8在小鼠体内的生物分布研究表明，2 min时的初始脑摄取较高。用SA 4503预处理导致脑血比显著降低（30分钟时为70%-75%）。ICR小鼠的离体放射自显影显示放射性示踪剂在富含σ 1受体的脑区中有较高的蓄积。这些发现表明[18 F] 8可能是进一步结构修饰的先导化合物，以开发潜在的σ 1受体脑显像剂。
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 σ1receptor ligands. All seven ligands exhibited nanomolar affinity for σ1receptors (Ki(σ1) = 0.47 – 12.1 nM) and moderate selectivity over σ2receptors (Ki(σ2)/Ki(σ1) = 2 – 44). Compound8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [18F]8was prepared via nucleophilic18F-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 [18F]8in 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 vivoautoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ1receptor-rich brain areas. These findings suggest that [18F]8could be a lead compound for further structural modifications to develop potential brain imaging agents for σ1receptors.