A thiourea-bridged 99mTc(CO)3-dipicolylamine-2-nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea-bridge to improve pharmacokinetics

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-09-10 DOI:10.1002/ddr.22258
Sweety Mittal, Chandan Kumar, Laxmi Jha, Madhava B. Mallia
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Abstract

The 2-nitroimidazole based 99mTc-radiopharmaceuticals are widely explored for imaging tumor hypoxia. Radiopharmaceuticals for targeting hypoxia are often lipophilic and therefore, show significant uptake in liver and other vital organs. In this context, lipophilic radiopharmaceuticals with design features enabling faster clearance from liver may be more desirable. A dipicolylamine-NCS bifunctional chelator that could generate a thiourea-bridge up on conjugation to primary amine bearing molecule was used to synthesize a 2-nitroimidazole-dipicolyl amine ligand for radiolabeling with 99mTc(CO)3 core. Corresponding Re(CO)3-analogue was prepared to establish the structure of 2-nitroimidazole-99mTc(CO)3 complex prepared in trace level. The 2-nitroimidazole-99mTc(CO)3 complex showed a hypoxic to normoxic ratio of ~2.5 in CHO cells at 3 h. In vivo, the complex showed accumulation and retention in tumor with high tumor to blood and tumor to muscle ratio. The study demonstrated the utility of metabolizable thiourea-bridge in 2-nitroimidazole-99mTc(CO)3 complex in inducing faster clearance of the radiotracer from liver. The dipicolylamine-NCS bifunctional chelator reported herein can also be used for radiolabeling other class of target specific molecules with 99mTc(CO)3 core.

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以肿瘤缺氧为靶点的硫脲桥接 99m锝(CO)3-二二甲胺-2-硝基咪唑复合物:利用可代谢的硫脲桥接改善药代动力学
基于 2-硝基咪唑的 99mTc 放射性药物被广泛用于肿瘤缺氧成像。以缺氧为靶点的放射性药物通常具有亲脂性,因此在肝脏和其他重要器官中会被大量吸收。在这种情况下,具有能更快从肝脏清除的设计特点的亲脂性放射性药物可能更为理想。我们利用一种能在与伯胺分子共轭时生成硫脲桥的双功能螯合剂,合成了一种用于以 99mTc(CO)3 为核心进行放射性标记的 2-硝基咪唑-二烷基胺配体。制备了相应的 Re(CO)3 类似物,以确定痕量制备的 2-硝基咪唑-99mTc(CO)3 复合物的结构。2-nitroimidazole-99mTc(CO)3 复合物在 CHO 细胞中的缺氧与常氧比为 2.5。研究表明,2-硝基咪唑-99mTc(CO)3 复合物中可代谢的硫脲桥可加快放射性示踪剂从肝脏中清除的速度。本文报告的二咪唑胺-NCS 双功能螯合剂还可用于以 99mTc(CO)3 为核心对其他类靶标分子进行放射性标记。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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