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 σ₁ receptor ligands. All seven ligands exhibited nanomolar affinity for σ₁ receptors (K_i(σ₁) = 0.61 – 12.0 nM) and moderate selectivity toward σ₂ receptors (K_i(σ₂)/ K_i(σ₁) = 2 – 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [¹⁸F]8 was prepared via nucleophilic ¹⁸F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of >99%, and molar activity of 94 – 121 GBq/μmol. Biodistribution studies of [¹⁸F]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 σ₁ receptor-rich brain areas. These findings suggest that [¹⁸F]8 could be a lead compound for further structural modification to develop potential brain imaging agent for σ₁ receptors.

我们报告的设计，合成，和一系列1-氧杂-8-氮杂螺的评价[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。所有七个配体显示出纳摩尔亲和力σ ₁受体（ķ_我（σ ₁）= 0.61 - 12.0 1nM）和适中选择性朝向σ ₂受体（ķ_我（σ ₂）/ ķ_我（σ ₁）= 2 - 44）。选择了在这些配体中具有最佳选择性的化合物8进行放射性标记和进一步评估。放射性配体[ ¹⁸ F] 8该化合物是通过相应甲苯磺酸酯前体的亲核¹⁸ F取代制备的，总的分离放射化学产率为12-35％，放射化学纯度> 99％，摩尔活性为94 – 121 GBq /μmol。[ ¹⁸ F] 8在小鼠中的生物分布研究表明，在2分钟时高的初始大脑摄取。用SA4503进行预处理可显着降低脑血比（30分钟时为70％-75％）。离体在ICR小鼠放射自显影证明σ放射性示踪剂的高积累₁富含受体的脑区域。这些发现表明[ ¹⁸ F] 8可以作为进一步结构修饰铅化合物开发潜在脑成像剂σ ₁受体。