核素标记番泻苷元A构建坏死靶向分子探针评价心肌活性及其机制研究

Revascularization is an important means of treatment for coronary heart disease (CHD), but could do harm to patients already with extensive irreversible myocardial infarction. Therefore, clinical guidelines emphasize myocardial viability assessment before cardiac intervention. Currently, imaging modalities rely on the uptake of tracers or contrast agents by viable cardiomyocytes for viability evaluation, which are affected by the blood perfusion, metabolism, and ischemic stages. Such uptake in viable tissue may even worsen the heart failure. Nevertheless, the molecular probes that target necrotic myocardium for differentiation of myocardial viability can avoid these problems, which is the focus of this project. Previously, we discovered that certain dianthrone compounds featured targetability to necrotic myocardium. By screening and comparing subtypes of dianthrones, we further found that median dianthrone such as Sennidin A displays good pharmacokinetics and necrosis-targetability. The aim of this project is to create 99mTc labeled Sennidin A as a novel necrosis-targeting probe, to study its molecular imaging property and to explore its applications in scintigraphic myocardial viability assessment and in nuclear medicine or molecular imaging research. In addition, we will study the mechanisms of its necrosis-targeted binding specifically to DNA exposed from necrotic tissue by using molecular probes constructed to bind and/or block interaction with DNA, etc. This project is intended to offer a brand new imaging setup for determination of myocardial viability. Such in-depth research is deemed to provide fundamental and practical bases to diagnostic and therapeutic strategies for precision medicine on CHD.

心肌血运重建是冠心病治疗的有效手段，但对于有大量坏死心肌形成的患者，会加重其心肌梗死程度，因此临床指南要求术前进行心肌活性评价。目前通过存活心肌摄取对比剂成像来判断心肌活力，结果易受多种因素影响，且对比剂的摄入会加重心衰。而靶向坏死心肌的分子探针成像可避免以上问题，成为研究的重要方向。本课题组前期研究发现二蒽醌类化合物具有坏死心肌靶向性，对各亚型二蒽醌筛选比较后，发现中位二蒽酮靶向性和药代动力学性质更佳。本项目拟以99mTc标记番泻苷元A构建分子探针，建立其对坏死心肌成像核医学方法，并研究其分子影像规律，探索该方法对心肌活性评价的诊断意义。同时研究二蒽醌与DNA结合的方式与强度，通过蒽醌阻断结合等实验，研究其靶向性与其特异性结合到坏死组织暴露DNA之间的关系，探索其坏死组织靶向机理。本项目可为心肌活性判断提供一个崭新的成像方法，该方法的深入研究势必为临床冠心病的诊治提供新的策略和理论依据。

心肌血运重建是冠心病治疗的有效手段，但对于有大量坏死心肌形成的患者，会加重 其心肌梗死程度，因此临床指南要求术前进行心肌活性评价。目前通过存活心肌摄取对比 剂成像来判断心肌活力，结果易受多种因素影响，且对比剂的摄入会加重心衰。而靶向坏死心肌的分子探针成像可避免以上问题，本课题组前期研究在二蒽醌类化合物具有坏死心肌靶向性，发现番泻苷A靶向性和药代动力学性质更佳，本项目以99mTc标记番泻苷元A构建分子探针99mTc-SA1，该探针对坏死心肌体内3 h能够成像坏死心肌，实现快速成像心肌活性评价具有良好的临床意义。通过阿霉素阻断结合等实验，确定其靶向性与其特异性结合到坏死组织暴露DNA上的靶向机理，并进一步发现二蒽醌与DNA结合的沟槽结合方式与强度。本项目可为心肌活性判断提供一个崭新的成像方法，该方法的深入研究势必为临床冠心病的诊治提供新的策 略和理论依据