针对心室重构关键靶点的新型核素探针构建与显像研究

Ventricular remodeling (VR) develops in response to a variety of forms of myocardial injury and increased wall stress, is one of the major reason for heart failure (HF). Several underlying mechanisms of HF have been identified that interact markedly in the pathophysiology of dysfunctional myocardium, including abnormalities in coronary flow, myocardial blood flow, cell metabolism, and sympathetic innervation of the myocardium. In this project, cardioprotective mechanisms in VR will be evaluated through new targeting probes. The relationship of CXCR4 and GLP1 receptors with VR have been reported in the literatures. Here, we design several radiolabeled probes targeting these targets in VR and expected for PET imaging. For CXCR4 receptor targeting, two kinds of ligand were designed and radiolabeled with 18F, one is the analogue of AMD3465, another is the derivative of cyclic pentapeptide FC131. While for GLP-1 receptor, a very potent ligand based on peptide EM3106B was selected and radiolabeled with 18F. The brand new radiolabeling stratagem of [18F]TiF- and [18F]ZrF-DOTA will be tested in this project. Ti4+ and Zr4+ are the best metal ions for F-18. They are close to or better than Al3+ for F-18 labeling efficiency. Based on the preparation of radiolabeled probes, the expression of CXCR4 and GLP1 receptors in myocardial infarction models will be quantitated with microPET imaging. The cardioprotective mechanisms and the relationship of these targets will be studied and compared via PET imaging. The results of this research project will provide new and efficient radioprobes for PET imaging of VR applications.

心室重构是导致心力衰竭的重要因素之一，心衰预后差，死亡率高，已经成为一个严重的公共卫生问题。核医学影像手段的高灵敏度使其成为心血管疾病诊断首选。本项目首要目的是构建针对心室重构关键靶点的核素探针并进行显像研究。研究表明，趋化因子CXCR4受体和胰高血糖素样肽-1（GLP-1）受体均与心室重构过程中的心肌保护机制有关，本项目分别设计了针对CXCR4和GLP-1的受体的放射性标记新结构探针。在成功制备放射性探针的基础上，预期通过PET显像方法研究，建立基于影像的受体鉴别与定量方法，综合比较各靶点在心室重构发展过程中的变化关系，探索心室重构中的心肌保护机制，实现心衰疾病的早期诊疗和预后评估，最终达到降低心衰死亡率的目的。

心室重构是导致心力衰竭的重要因素之一，心衰预后差，死亡率高，已经成为一个严重的公共卫生问题。核医学影像手段的高灵敏度使其成为心血管疾病诊断首选。本项目针对心室重构关键靶点进行核素标记分子探针的研制并进行显像研究。在创新放射性碘标记方法的基础上，获得了两种靶向趋化因子CXCR4受体的核素探针、一种HER2受体选择性的放射性小分子探针、一种全新结构的18F标记正电子心肌灌注显像剂和一种放射性标记小分子心血池显像剂。同时，开发了与心室重构过程中的心肌保护机制有关的NO信号分子响应光学探针和与心肌损伤保护有关的活性氧ROS响应放射性/光学双模探针。在成功制备以上分子探针后，通过体外细胞评价以及活体SPECT/PET显像研究，确证了所研制分子探针对响应靶点的特异性和亲和力，初步建立了基于影像的受体鉴别与定量方法。后续研究将基于分子探针的突破进行各靶点在心室重构发展过程中的变化关系比较并探索心室重构中的心肌保护机制，实现心衰疾病的早期诊疗和预后评估。