新型MRI肝胆特异性对比剂Gd-chelate-CSar的研究

Hepatobiliary-specific contrast agent is of great value for MRI in the diagnosis of liver cancer, but these existing contrast agents are still limited in a low hepatobiliary targeting, high renal excretion and long delay time of hepatobiliary imaging. Because of its high hepatobiliary targeting, rapid blood-to-liver uptake and liver-to-bile excretion, intestinal excretion in a prototype and other advantages, a small molecule cholylsarcosine (CSar) could be used as targeting structure matrix to develope a novel hepatobiliary-specific MRI contrast agent with high performance. On the basis of the successful design and synthesis of new compounds of hepatobiliary disease, we designed these Gd-chelate coupling CSar compounds of Gd-DTPA-CSar and Gd-EOB-DTPA-CSar. We want to explore the optimal synthesis route of these compounds. Thus, to explore the clinical potential of these compounds, conventional hepatobiliary-specific MRI contrast agent (Gd-EOB-DTPA) will be used as control to compare the stability, cytotoxicity, acute toxicity, in vivo distribution and animal MRI (pharmacokinetics, liver injury model and VX2 liver cancer model). This project will provide a theoretical basis for the construction of a novel MRI contrast agent with a high quantity and safety.

肝胆特异性对比剂在MRI诊断肝癌中具有重要的价值，但是，现有此类对比剂尚有肝胆靶向性不高、肾排泄多、肝胆显像延迟时间长等缺点。小分子胆酰肌氨酸（CSar）具有肝胆靶向性高、血浆-肝细胞转运快、肝细胞-胆汁分泌迅速、经肠道原型排泄等优点，可作为母体靶头构建新型高性能MRI肝胆特异性对比剂。因此，本研究基于前期成功设计并合成肝胆疾病方面新型化合物的工作基础，将Gd螯合物与CSar进行偶联，设计新型对比剂Gd-DTPA-CSar和Gd-EOB-DTPA-CSar，探索该类化合物的最佳合成路径。进而，与常规肝胆特异性对比剂Gd-EOB-DTPA对照，进行稳定性、细胞毒性、急性毒性、体内分布和动物MRI研究（药代动力学、肝损伤模型和VX2肝癌模型），探索其潜在临床价值。这将为构建高品质、安全性有保障的新型MRI对比剂提供理论依据。

本课题研发一种新型磁共振肝胆特异性对比剂，通过合理设计新型对比剂的分子结构来进一步提高肝胆特异性、优化体内分布、提高磁共振检查诊断正确性、缩短检查时间等目的。在原计划基础上，本课题组进一步探索、修改和完善化合物设计和合成方案，获得新型磁共振肝胆特异性对比剂（Gd-DOTA-CSar），进行了体外理化性质实验与动物体内实验，获得了预期实验成果。主要研究发现包括：（1）在尽可能保留胆酰肌氨酸活性基团的基础上，建立了可行性高的合成技术。（2）体外稳定性实验证明Gd-DOTA-CSar在室温条件下在多种溶质中稳定性好。（3）细胞毒性实验证明Gd-DOTA-CSar毒性较小。（4）Gd-DOTA-CSar应用于健康小鼠磁共振显像及大鼠体内分布实验表明目标产物具有高的肝胆特异性，肝/肾分布比例高，且胆道显影时间明显提前。（5）肝损伤模型小鼠与肝癌模型裸鼠磁共振显像证明了Gd-DOTA-CSar可用于评估肝功能损伤和诊断肝脏肿瘤。本研究证实了此类对比剂的临床应用潜能，对进一步研发和临床转化提供了科学依据。

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