Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy
Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy
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DOI：
10.1016/j.nucmedbio.2015.07.001
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发表时间：
2015-11-01
影响因子：
3.1
通讯作者：
Odani, Akira
中科院分区：
文献类型：
--
作者：
Ogawa, Kazuma;Mizuno, Yoshiaki;Odani, Akira
Sigma受体在多种人类肿瘤中过表达，使其成为放射性核素受体治疗的潜在靶点。我们之前已经合成并评价了I-131标记的(+)-2-[4-（4-碘苯基）哌啶醇]环己醇[(+)-[I-131]pIV]，它对sigma受体具有高亲和力。因此，(+)-[I-131]pIV可显著抑制荷瘤小鼠的肿瘤细胞增殖。在本研究中，我们报道了(+)-[At-211]pAtV的合成和体外和体内表征，这是一种At-211标记的sigma受体配体，在α -放射性核素受体治疗中有潜在的应用。方法：采用标准卤化反应制备放射性标记的sigma受体配体(+)-,[At-211]pAtV，经HPLC纯化，放射化学产率91%，纯度98%。测定了（+）[At-211]pAtV的分配系数。使用(+)-[At-211]pAtV和(+)-[I-125]pIV的混合溶液进行细胞摄取实验和体内生物分布实验；表达高水平sigma受体的人类前列腺癌细胞系DU-145和DU-145荷瘤小鼠。结果：(+)-[At-211]pAtV的亲脂性与(+)-[I-125]pIV相似。注射后1 h， （+）[at -221]pAtV和(+)-[I-125]pIV在DU-145荷瘤小鼠中的细胞摄取和生物分布模式也相似。也就是说，（+）[At-211]pAtV通过与sigma受体结合在肿瘤中表现出高度的摄取和保留。结论：（+）[At-221]pAtV可作为α -核素受体治疗的新型药物。(C) 2015爱思唯尔公司版权所有。
Introduction: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized, and evaluated I-131-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[I-131]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[I-131]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[At-211]pAtV, an At-211-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy.Methods: The radiolabeled sigma receptor ligand (+)-,[At-211]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)[At-211]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[At-211]pAtV and (+)-[I-125]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice.Results: The lipophilicity of (+)-[At-211]pAtV was similar to that of (+)-[I-125]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1 h post-injection were also similar between (+)[At-221]pAtV and (+)-[I-125]pIV. Namely, (+)[At-211]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors.Conclusion: These results indicate that (+)[At-221]pAtV could function as an new agent for alpha-radionuclide receptor therapy. (C) 2015 Elsevier Inc. All rights reserved.