†Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, POB 510119, D-01314 Dresden, Germany.
‡Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
J Med Chem. 2015 Jul 23;58(14):5395-407. doi: 10.1021/acs.jmedchem.5b00593. Epub 2015 Jul 2.
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). [(18)F]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 [(18)F]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.
我们报告了一系列新型低亲脂性哌啶化合物的合成和评估，它们是 σ1 受体配体。8-(4-(2-氟乙氧基)苄基)-1,4-二恶-8-氮杂螺[4.5]癸烷（5a）对 σ1 受体具有高亲和力（K(i) = 5.4 ± 0.4 nM），对 σ2 受体（30 倍）和囊泡乙酰胆碱转运体（1404 倍）具有选择性。[(18)F]5a 采用自动化合成模块中的一锅两步标记程序进行制备，放射化学纯度>95%，比活度为 25-45GBq/μmol。细胞结合、生物分布和阻断实验的放射自显影表明，[(18)F]5a 在体外和体内与 σ1 受体具有特异性结合。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，该示踪剂在人癌和黑色素瘤中有高积累。用氟哌啶醇治疗可显著减少放射性示踪剂在肿瘤中的积累。这些发现表明，具有合适亲脂性和适当 σ1 受体亲和力的放射性示踪剂可用于肿瘤成像。
