In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting
In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting
复制标题
Tc-99m标记的氮杂二苯并环辛炔-MAMA和2-硝基咪唑-叠氮之间的体内点击反应用于肿瘤缺氧靶向
DOI：
10.1016/j.bmcl.2015.09.004
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发表时间：
2015
影响因子：
2.7
通讯作者：
Taiwei Chu
中科院分区：
文献类型：
--
作者：
Wenjing Sun;Taiwei Chu
tc -99m标记的2-硝基咪唑是一种传统的用于单光子发射计算机断层扫描（SPECT）的实体肿瘤缺氧显像剂，由于大配体和金属放射性核素的存在，硝基咪唑的生物活性降低，显示出较低的肿瘤与非肿瘤比率。为了解决这一普遍问题，采用了一种基于点击化学的预靶向策略（菌株促进环辛基叠氮化环加成）。合成了功能键合子作为预靶向成分：2-硝基咪唑（2NIM-Az）叠氮基团作为肿瘤缺氧靶向，单胺单酰胺二硫醇配体偶氮二苯并环辛（AM）在体内作为叠氮的放射性标记和结合基团。2NIM-triazole-MAMA通过体外点击反应得到，反应速率常数为0.98 M−1s−1。AM和2im -三唑- mama用Tc-99m放射性标记。研究了S180肿瘤昆明小鼠缺氧预靶向生物分布；99mTc-AM和99mtc -三唑- 2nim分别作为空白对照和常规对照。与对照组相比，预靶向实验在肿瘤中表现出最好的放射性吸收和保留，肿瘤与肌肉和肿瘤与血液的比率更高（注射99mtc复合物后8 h分别高达8.55和1.44）。预靶向策略在一定程度上保护了硝基咪唑的生物活性，从而为肿瘤缺氧spect显像剂的开发提供了一种创新途径。
The bioactivity of nitroimidazole in Tc-99m-labeled 2-nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this general problem, a pretargeting strategy based on click chemistry (strain-promoted cyclooctyne-azide cycloaddition) was applied. The functional click synthons were synthesized as pretargeting components: an azide group linked to 2-nitroimidazole (2NIM-Az) serves for tumor hypoxia-targeting and azadibenzocyclooctyne conjugated with monoamine monoamide dithiol ligand (AM) functions as radiolabeling and binding group to azides in vivo. 2NIM-triazole-MAMA was obtained from in vitro click reaction with a reaction rate constant of 0.98 M−1s−1. AM and 2NIM-triazole-MAMA were radiolabeled with Tc-99m. The hypoxia-pretargeting biodistribution was studied in Kunming mice bearing S180 tumor;99mTc-AM and99mTc-triazole-2NIM were used as blank control and conventional control. Compared to the control groups, the pretargeting experiment exhibits the best radio-uptake and retention in tumor, with higher tumor-to-muscle and tumor-to-blood ratios (up to 8.55 and 1.44 at 8 h post-99mTc-complex-injection, respectively). To some extent, the pretargeting strategy protects the bioactivity of nitroimidazole and therefore provides an innovative approach for the development of tumor hypoxia-SPECT imaging agents.