以内皮素A受体为靶点的肺血管重构分子显像研究

Pulmonary vascular remodeling is the characteristic pathological changes which led to the formation and development of pulmonary arterial hypertension. Endothelin and their receptors play a key role in it. In particular, endothelin A receptor mediates pulmonary vasoconstriction and cell proliferation, that directly promotes the formation of pulmonary vascular remodeling and pulmonary hypertension. High expression of endothelin A receptor has become a characteristic molecular marker of pulmonary vascular remodeling and a novel target for drug treatment which aim to reverse pulmonary vascular remodeling. Although it has been highlighted, but there is still lack of effective detection methods. This project will develop a new endothelin A receptor molecular probe [18F] FDIOBA which have not only high affinity to receptors, but also faster blood clearance and lower lung background. [18]FDIOBA PET imaging will perform in rat models with pulmonary hypertension or with drug intervention for a real-time quantitative detection of endothelin A receptor expression level and dynamic change in vivo. Its reliability will be confirmed by pathological and immunohistochemical examination. To establish a new method of molecular imaging, which can be effectively used for the diagnosis of pulmonary vascular remodeling and evaluation for drug curative effect, is helpful for solving the problem currently existing in the clinic.

肺血管重构是导致肺动脉高压形成和发展的特征性病理变化，内皮素及其受体在其中起到关键性的作用，特别是内皮素A受体所介导的肺血管收缩和细胞增殖作用，直接促进了肺血管重构和肺高压的形成。高度表达的内皮素A受体已成为肺血管重构的特征性分子位点和以延缓或逆转肺血管重构为目标的药物治疗的新靶点，备受关注，但目前仍缺乏有效的检测手段。本项目将制备并筛选出一种新型的内皮素A受体分子探针[18F]FDIOBA，它不仅具有高度的受体结合能力，且血液清除快，肺本底低。利用肺动脉高压及药物干预大鼠模型进行[18F]FDIOBA PET显像，对内皮素A受体的表达水平及动态变化，实现活体、实时的定量检测，其可靠性以病理及免疫组化检查加以证实，从而建立一种新的分子显像方法，能够有效地用于肺血管重构的诊断和相关药物的疗效评价，解决目前临床上存在的难题。

肺血管重构是肺动脉高压的主要病理特征，目前存在的主要临床难题是缺乏肺血管重构的无创性影像学诊断技术以及减缓或逆转肺血管重构的有效药物治疗手段。本项目针对上述问题，开展了两方面的研究：一是建立评价肺血管重构的分子影像诊断新技术；二是初步探讨应用胰高血糖素样肽-1（GLP-1）受体激动剂减缓或逆转肺血管重构的治疗作用。本项目成功构建了针对肺血管重构特征性靶点内皮素受体的两种放射性核素分子探针18F-FDIOBA和18F-FMCP3T，分别建立了前体物质合成方法和放射性核素标记技术，并对大鼠肺动脉高压模型进行了MicroPET显像，结果表明：动物模型肺组织对两种分子探针的摄取均显著升高。免疫组化检测显示：MicroPET显像反映了肺血管内皮素A受体表达的升高，与病理显示的肺血管增生相一致。本项目还利用GLP-1受体激动剂艾塞那肽对肺高压大鼠模型进行干预治疗，结果表明：治疗干预后，肺血流动力学明显改善，病理检测证实肺血管增生和炎症显著减轻，目前认为GLP-1受体激动剂有可能通过调节细胞代谢，抑制细胞糖酵解，促进线粒体功能，恢复细胞代谢效率，从而减轻炎症及细胞增生，达到缓解或逆转肺动脉高压的治疗作用。初步尝试应用反映糖代谢功能的18F-FDG MicroPET显像观察GLP-1受体激动剂的治疗效果，发现治疗干预后肺组织18F-FDG摄取明显降低，18F-FDG PET显像有希望成为有效的疗效评价手段。上述研究为建立以肺血管重构为靶点的肺动脉高压分子影像诊断新技术和代谢调节治疗新策略提供了实验基础。