F-18-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a sigma(1) Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent
F-18-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a sigma(1) Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent
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F-18 标记的 1,4-二氧杂-8-氮杂螺[4.5]癸烷衍生物：作为有效肿瘤显像剂的低亲脂性 sigma(1) 受体放射性配体的合成和生物学评价
DOI：
10.1021/acs.jmedchem.5b00593
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发表时间：
2015
影响因子：
7.3
通讯作者：
Jia Hongmei
中科院分区：
文献类型：
--
作者：
Xie Fang;Bergmann Ralf;Kniess Torsten;Deuther-Conrad Winnie;Mamat Constantin;Neuber Christin;Liu Boli;Steinbach Joerg;Brust Peter;Pietzsch Jens;Jia Hongmei
我们报道了一系列新型低亲脂性的哌啶类化合物作为σ-1受体配体的合成和评价。8-(4-(2-Fluoroethoxy)benzyl)-1，4-dioxa-8-azaspiro[4.5]decane(5a)对σ-1受体具有高亲和力(Ki=5.4±0.4 nM)，对σ-2受体和囊泡乙酰胆碱转运体的选择性分别为30倍和14.0 4倍。[18F]5A在自动合成模块中使用一锅两步标记程序制备，放化纯度为~gt；95%，比活度为25-45GBq/μ摩尔。细胞结合、生物分布和放射自显影阻断实验表明，[18F]5atoσ-1受体在体外和体内都有特异性结合。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，在人类癌症和黑色素瘤中高度聚集。氟哌啶醇治疗可显著减少放射性示踪剂在肿瘤中的蓄积。这些结果表明，对σ-1受体具有适当亲脂性和亲和力的放射性示踪剂可用于肿瘤显像。
We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (Ki= 5.4 ± 0.4 nM) for σ1receptors and selectivity for σ2receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [18F]5awas 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]5ato σ1receptors 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 σ1receptors could be used for tumor imaging.