We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ₁ receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K_i = 5.4 ± 0.4 nM) for σ₁ receptors and selectivity for σ₂ receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [¹⁸F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25–45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [¹⁸F]5a to σ₁ receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ₁ receptors could be used for tumor imaging.

中文翻译：

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¹⁸ F-标记的1,4-二氧杂-8-氮杂螺[4.5]癸烷衍生物：一个σ的合成和生物学评价₁受体放射性配体与低亲脂作为有效的肿瘤显像剂

我们报告低亲脂性系列新颖的哌啶化合物作为σ的合成和评价₁受体配体。8-（4-（2-氟乙氧基）苄基）-1,4-二氧杂-8-氮杂螺[4.5]癸烷（5A）具有高亲和力（ķ_我= 5.4±0.4纳米）为σ _1个受体和选择性σ ₂受体（30倍）和水泡乙酰胆碱转运蛋白（1404倍）。[ ¹⁸ F] 5a是在自动合成模块中使用一锅，两步标记程序制备的，放射化学纯度> 95％，比活度为25-45 GBq /μmol。细胞结合，生物分布和放射自显影与阻断实验表明[¹⁸ F]图5a到σ _1种受体在体外和体内。使用小鼠肿瘤异种移植模型的小动物正电子发射断层扫描（PET）成像显示在人类癌和黑色素瘤中高积累。氟哌啶醇的治疗显着减少了放射性示踪剂在肿瘤中的积累。这些结果表明与合适的亲脂性和适当的亲合力放射性示踪剂为σ _1个受体可用于肿瘤成像。