Development and Evaluation of Novel 18F-PET Tracers for Imaging of Cardiac Angiotensin II Type 1 Receptor

肾素-血管紧张素-醛固酮系统(RAS)不仅在心血管系统中发挥重要作用，而且在单个器官中也发挥着重要作用。这些器官中存在对功能调节至关重要的局部RAS。因此，为了了解这些局部系统，特别是心脏局部系统的病理生理机制，进一步指导和优化现有的抗RAS药物的应用，迫切需要发展非侵入性的方法来识别和监测这些局部系统的功能。通过在正电子发射断层扫描中应用放射性标记的血管紧张素II 1型受体(AT1)拮抗剂，可以对RAS进行临床评估，为心血管疾病患者的治疗提供有价值的信息。研究科学家已报道的放射性示踪剂并不理想，并在不同程度上显示出局限性。因此，通过构效关系分析和合理的化合物设计，我们希望从临床使用的AT1拮抗剂中开发出新型的18F-示踪剂。这些放射性示踪剂有望表现出与它们的母体药物分子，如valsartan和losartan类似的特异性和选择性。这些示踪剂的前体将被合成和表征。将首先生产冷化合物并用于放射配基结合分析，以确认AT1和AT2受体亚型具有相似的结合和选择性。然后通过相关程序获得18F标记的靶向示踪剂。为了评价靶向放射性示踪剂在体内的性质和可行性，将它们注射到大鼠体内；评估生物分布和代谢，并与母体化合物进行比较。此外，还将进行与AT1受体拮抗剂竞争的选择性阻断研究。利用小动物PET研究，上述研究将直接可视化，为进一步研究其在心脏或其他器官中的代谢、应用及其在个性化医学中的应用潜力奠定基础。

The renin-angiotensin-aldosterone system (RAS) plays an important role not only in cardiovascular system, but also in individual organs. There are local RASs in these organs being critical for functional regulations. Therefore, in order to understand the pathophysiology of these local systems, especially in the heart, and for further guidance and optimization of the application of currently available anti-RAS therapeutics, it is urgent to develop non-invasive methods to identify and monitor the functions of these local systems.By applying radiolabelled angiotensin II type 1 receptor (AT1) antagonists in positron emission tomography (PET) scan, the RAS can be evaluated clinically and provide valuable information for treatment of patients with cardiovascular diseases. The radiotracers that have been reported by research scientists are not ideal and show limitations on different levels. Thus, through structure-activity relationship analysis and rational compound design we want to develop novel 18F-tracers being derived from AT1 antagonists used clinically. These radiotracers are expected to show similar specificity and selectivity as their parent drug molecules, e.g. valsartan and losartan.The precursors of such tracers will be synthesized and characterized. Cold compounds will first be produced and used in radioligand binding assay to confirm similar binding and selectivities at AT1 and AT2 receptor subtypes. The target 18F-labelled tracers will then be obtained applying related procedures.To evaluate the properties and feasibility of target radiotracers in vivo, they will be injected into rats; biodistribution and metabolism will be assessed and compared with parent compounds. Moreover, selective blocking studies by competing with reference AT1 antagonists will also be performed. Using small animal PET study, the above-mentioned studies will be directly visualized for further investigation of their metabolism, application in the heart or other organs and the potential for their application in personalized medicine.