磁共振成像法研究氨基酸衍生物修饰DTPA顺磁金属配合物的造影效果及分子识别机理

Magnetic resonance imaging (MRI) is at present well established as a safe and efficient imaging technique for the human body in clinical diagnosis.In the clinical MRI, more than 30% of the used to improve diagnosis contrast image contrast.Therefore, studying MRI contrast agents is more important. Gd-DTPA was well-established contrast agent in clinical use for MRI due to its high relaxivity, high chemical stability and low toxicity. However, its passive and nonspecific distribution in vivo limits its utility in focal lesion detection, moreover, its ionic characteristic leads to some side effects associated with its hyperosmolality at clinical dose. So, it has been one of both the most attractive and challenging tasks in this area in attempts to decrease the side effects and improve the tissue-and/or organ-specificity. Experience of pharmaceutical research revealed when a drug molecule with hydrophily and lipotropy which has amphipathy characteristics when it will tend to be liver uptake, such drugs will be targeted to the liver tissue. If the carboxyl of amino acid modified in lipotropy , while the amino modified in hydrophily, then, the ligand simultaneously satisfy amphipathy characteristics. Predictably, the paramagnetic metal complexes of ligand will be targeted to the liver tissue. The interest of the project is chiefly concentrated on soluble paramagnetic metal complexes with ligands from DTPA and amino acid derivatives as potential MRI contrast agent based on an analysis of the present situation of research on this subject. The structure-activity relationship will be studied extensively in order to explore molecular recognition mexichanism of the complexes. Toxicity and biological activity also will be studied in order to provide necessary theoretical basis and the reference data for the exploitation of new MRI contrast agent.

在临床的MRI中，有30%以上使用了造影剂来提高图像对比度。目前临床上常用的造影剂Gd-DTPA，虽能满足一些诊断要求，但其没有靶向性，且有一定的毒副作用。药物研究的经验规律揭示当药物分子同时具有亲脂亲水组分即具有两亲性特征时它将倾向于被肝脏摄取，此类药物分子将对肝组织有靶向性。如果将氨基酸的羧基修饰成亲脂基团，而氨基与DTPA的羧基形成酰胺，那么，此类配体同时满足两亲性特征。可以预见，其顺磁金属配合物将对肝组织有靶向性。本项目拟设计合成一系列氨基酸衍生物修饰DTPA的顺磁金属配合物作为研究的目标分子，通过弛豫增强方法系统的研究氨基酸种类及所修饰基团的不同对弛豫性能的影响，阐明其构效关系；并用磁共振成像法分析配合物对不同器官的选择性，探索其靶向分子识别机理。筛选具有高弛豫效率的配合物进行动物造影实验，全面评价其造影效果、毒性和生物活性，为开发新型MRI造影剂提供必要的理论依据和参考数据。

临床上常用的造影剂Gd-DTPA，虽能满足一些诊断要求，但其没有靶向性，且有一定的毒副作用。药物研究的经验规律揭示当药物分子同时具有亲脂亲水组分即两亲性特征时它将倾向于被肝脏摄取，此类药物分子将对肝组织有靶向性。如果将氨基酸的羧基修饰成亲脂基团，而氨基与DTPA的羧基形成酰胺，此类配体同时满足两亲性特征。本项目设计合成了一系列含有过渡金属离子Gd、Mn的氨基酸衍生修饰DTPA的顺磁配合物作为研究的目标分子，通过弛豫增强方法系统的研究氨基酸种类及所修饰基团的不同对弛豫性能的影响，结果表明：此类配合物中Gd和Mn的中性配合物的弛豫效率都较目前临床上常用的造影剂（Gd-DTPA)的弛豫效率高，而且有很好的生物活性，还能与DNA以插入方式结合。此外，采用Annexin V-FITC/PI 双染法细胞凋亡检测试剂盒，通过流式细胞仪检测了配合物对氧化应激状态下细胞凋亡的影响，研究表明，此类配合物的毒性都比较低。鉴于本项目设计合成的氨基酸衍生物修饰DTPA的顺磁金属配合物具有良好的水溶性，高的驰豫效率，低的毒性，且合成方便、价廉，易于大量制备，有望成为有潜在应用前景的MRI造影剂。也为开发新型MRI造影剂提供必要的理论依据和参考数据。这对总结指导合成 MRI 造影剂的规律，发展和开发这类 MRI 造影剂有重要的理论和现实意义。