手性DOTA及NOTA在磁共振成像和放射诊疗中的应用

目前临床上使用的钆（Gd）基MRI造影剂的安全性问题越来越突显，提高Gd配合物的稳定性是解决该问题的关键。放射性金属离子与抗体类分子相结合的放射免疫诊疗可诱导癌症患者体内免疫激活，抑制肿瘤转移及复发，但目前线型的DTPA配合物可产生金属游离导致脱靶毒性，而环型DOTA配体与放射性金属离子标记需要在高温下进行。如何既实现温和标记，又提高配合物稳定性，是MRI造影剂及核药领域需要解决的关键科学问题。手性大环类配体具有预组织的空腔结构，可降低配位反应吉布斯自由能，获得更加温和的标记条件，同时所得手性配合物的结构刚性增强，稳定性大幅度提高。本项目拟开发一系列手性DOTA及NOTA金属离子配体及配合物，并与功能性分子（如多肽、纳米抗体、近红外分子）相结合，开发具有靶向性、响应性、多模态或多功能的MRI造影剂及核药。该项目的实施，可进一步推动分子影像学的发展，以及各种成像与治疗技术的结合，意义重大。

The safety issues of gadolinium (Gd)-based MRI contrast agents currently used in clinical practice have become more and more prominent. Improving the stability of Gd complexes is the key to solve this problem. Radioimmunotherapies combine radioactive metal ions and antibodies, which can induce immune activation in cancer patients, therefore inhibiting tumor metastasis and recurrence. However, the radiometal complexes of linear DTPA chelator can release free metal ions which results in off-target toxicity, while using cyclic DOTA as chelator needs high-temperature reaction condition. So how to achieve mild labeling condition and improve the stability of complexes in the meantime is a key scientific problem in the field of MRI contrast agents and radiopharmaceuticals. The chiral macrocyclic chelators have pre-organized cavities, which can reduce the Gibbs free energy of the complexation reaction, therefore obtaining milder labeling conditions, while the formed chiral complexes have much higher stability than the achiral complexes because of the improved structural rigidity. This project intends to develop a series of chiral DOTA and NOTA chelators and their metal complexes that were further combined with functional molecules (such as peptides, nanobodies, and near-infrared molecules), resulting in a series of targeted, responsive, multimodal or multifunctional MRI contrast agents and nuclear drugs. The implementation of this project will further promote the development of molecular imaging and the combination of various imaging and therapeutic technologies, which has great research and clinical application value.