高性能磁共振造影剂的设计合成及活体成像研究

The arising incidences of tumors and cardiovascular diseases present an unprecedented challenge for clinical diagnosis. Given the fact that current contrast agents for magnetic resonance imaging (MRI) are far from satisfactory for sensitive and accurate clinical diagnosis, this project is aimed at finding the rules behind structure-activity relationship of contrast agents for MRI, rationally synthesizing and modifying high-performance T1 contrast agents and T2 contrast agents, and eventually developing contrast agents for high-resolution magnetic resonance angiography (MRA) and for high-sensitive MRI of tumors. The rules regarding structure-activity relationship of contrast agents for MRI will offer theoretical basis and scientific foundation for further development of high-performance contrast agents. The sensitive and high-resolution in vivo MR imaging based on the next-generation high-performance contrast agents will provide solutions for early and accurate diagnosis of tumors and cardiovascular diseases.

当前磁共振造影剂的性能在灵敏度、分辨率和准确性远不能满足肿瘤和心血管疾病等的临床精确成像诊断需求。我们的前期研究发现造影剂的性能与其化学结构和表界面修饰有密切关系，为发展高性能造影剂以提高成像灵敏度和疾病诊断精确性提供了工作基础。本项目拟开展如下工作：（1）首先深入研究造影剂的构效关系和内在规律，理性设计合成多种高弛豫效能的T1明场造影剂和T2暗场造影剂，提高磁共振造影成像的灵敏度和分辨率；（2）然后合理修饰造影剂的表界面结构以优化其体内行为，通过体外实验和活体成像实验发展高性能造影剂；（3）最后将造影剂用于高灵敏磁共振肿瘤成像诊断和高分辨磁共振血管造影成像研究。本项目所揭示的磁共振造影剂构效关系本质规律将为进一步发展高性能造影剂提供理论基础和科学依据。本项目所发展的基于高性能造影剂的磁共振成像将为肿瘤和心血管疾病的早期精确诊断提供有效方案。

本项目的主要研究目标是探究磁共振造影剂结构与性能的内在本质规律，并理性设计合成高性能磁共振成像造影剂。在此项目的资助下，我们围绕肿瘤精准诊疗和活体内重要特征分子信息可视化的关键科学问题，以磁共振分子探针为化学工具，开展生理病理特征分子信息的活体原位实时磁共振成像监测研究，顺利完成了项目预期目标。①阐明了磁共振造影剂结构与性能的关系，设计合成了系列高性能造影剂。②提出了T1磁共振信号激活响应策略，构建激活响应前药分子，实现肿瘤原位磁共振分子成像和有效干预。③发展了特异性响应19F磁共振探针，实现了生命体系病理特征分子信息的活体原位磁共振成像和监测。已在Chem，JACS，Angew Chem，Acc Chem Res，Adv Mater等国际重要学术期刊发表论文26篇。申请中国发明专利4项，其中授权2项。