新型核素 64Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究

doi:10.7503/cjcu20140438

高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (1): 87.doi: 10.7503/cjcu20140438

新型核素 ⁶⁴Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究

罗政¹, 朱华¹, 林新峰¹, 洪业¹, 肖绍文², 张强³, 褚泰伟³, 杨志¹()

1. 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 2. 放射治疗科, 北京 100142
3. 北京大学化学与分子工程学院, 北京 100871

收稿日期:2014-05-08 修回日期:2014-12-23 出版日期:2015-01-10 发布日期:2014-12-23
作者简介:联系人简介: 杨志, 男, 博士, 教授, 主要从事分子影像的基础与临床研究. E-mail: pekyz@163.com
基金资助:
国家自然科学基金(批准号: 81071198, 81172083, 81371592)和北京市自然科学基金(批准号: 7132040)资助.

Radio-labelling and Micro-PET Study of ⁶⁴Cu Labelled PnAO-1-(2-nitroimidazole) for Hypoxia Imaging^†

LUO Zheng¹, ZHU Hua¹, LIN Xinfeng¹, HONG Ye¹, XIAO Shaowen², ZHANG Qiang³, CHU Taiwei³, YANG Zhi^1,^*()

1. Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, 2. Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
3. College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

Received:2014-05-08 Revised:2014-12-23 Online:2015-01-10 Published:2014-12-23
Contact: YANG Zhi E-mail:pekyz@163.com
Supported by:
Supported by the National Natural Science Foundation of China(Nos. 81071198, 81172083, 81371592) and the Beijing Municipal Natural Science Foundation, China(No. 7132040).

摘要/Abstract

摘要：

采用新型核素 ⁶⁴Cu标记了含丙烯胺肟[PnAO(3,3,9,9-Tetramethyl-4,8-diazaundecane-2,10-dione Dioxime)]结构的硝基咪唑类乏氧显像剂PnAO-1-(2-nitroimidazole)[BMS181321], 通过优化反应条件, 于室温下反应10 min后即得到高放化纯度和高比活度的标记化合物 ⁶⁴Cu-BMS181321. 目标产物经放射性高效液相色谱检测验证和体外稳定性实验确认后, 通过尾静脉注射到人源胰腺癌(PANC-1细胞系)裸鼠体内, 分别于注射显像剂4和8 h后进行小动物正电子发射断层扫描显像(Micro-PET). 结果表明, 4 h左右肿瘤乏氧区域有良好的放射性浓聚. ⁶⁴Cu-BMS181321的合成及其分子显像研究开创了 ⁶⁴Cu标记硝基咪唑类乏氧显像剂进行乏氧显像的先例, 经进一步药物临床实验评价后, ⁶⁴Cu-BMS181321有望成为具有良好前景的PET乏氧显像药物.

关键词: 硝基咪唑, 64Cu, 正电子发射断层显像, 乏氧显像

Abstract:

Monitoring hypoxia is very important for tumor treatment, the ideal hypoxia imaging agents should have a relatively long half-life and specific to hypoxic cells. However, such an ideal imaging agent has not been developed until now. In order to develop an ideal imaging agent for monitoring hypoxia, nitroimidazole imaging agent PnAO-1-(2-nitroimidazole)[BMS181321] was synthesized and radiolabeled with ⁶⁴Cu for ⁶⁴Cu-BMS181321. The basic experimental process is as follows: the BMS181321 dissolved in sodium acetate buffer(pH=5.5) was added to the eluent of ⁶⁴CuCl₂, and the solution was stirred and placed at room temperature for 10 min. The labelling efficiency and radiochemical purity of ⁶⁴Cu-BMS181321 were all over 99%, determined by radio-HPLC. The ⁶⁴Cu-BMS181321 was stable in physiological saline for more than 15 h, which was a meaningful characteristic for clinical application. After quality control, 21.8 MBq of ⁶⁴Cu-BMS181321 was injected into human pancreatic cancer xenograft mouse models via tale vein. Positron emission tomography(PET) images were taken at 4 and 8 h after the injection. PET imaging in human tumor models was excellent compared with other PET hypoxia imaging agents. In brief, the research results suggest that ⁶⁴Cu-BMS181321 is potential for PET hypoxia imaging in clinical and should be further evaluated in clinic trial.

Key words: Nitroimidazole, 64Cu, Positron emission tomography, Hypoxia imaging

中图分类号:

O628
O652

TrendMD:

罗政, 朱华, 林新峰, 洪业, 肖绍文, 张强, 褚泰伟, 杨志. 新型核素 ⁶⁴Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究. 高等学校化学学报, 2015, 36(1): 87.

LUO Zheng, ZHU Hua, LIN Xinfeng, HONG Ye, XIAO Shaowen, ZHANG Qiang, CHU Taiwei, YANG Zhi. Radio-labelling and Micro-PET Study of ⁶⁴Cu Labelled PnAO-1-(2-nitroimidazole) for Hypoxia Imaging^†. Chem. J. Chinese Universities, 2015, 36(1): 87.

图/表 4

Scheme 1 Radio-labelling of 64Cu-BMS181321

Fig.1 Influences of reaction time(A) and pH(B) on the labelling efficiency at 25 ℃ The yield(%) means the labelling efficiency of 64Cu-BMS181321.

Fig.2 In vitro stability of 64Cu-BMS181321 conjugated in different solutions a. 0.9% NaCl; b. NaAc buffer(pH=5.5).

Fig.3 PET images of 64Cu-BMS181321 at 4 h(A—C) and 8 h(D—F) after intravenious injection The white arrow represents hypoxic tumor, and the violet arrow represents necrotic tumor. (A, D) Transverse plane; (B, E) coronal plane; (C, F) sagittal plane.

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新型核素 ⁶⁴Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究

Radio-labelling and Micro-PET Study of ⁶⁴Cu Labelled PnAO-1-(2-nitroimidazole) for Hypoxia Imaging^†

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