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起重要作用，而且在各个器官中也起重要作用。在这些机构中有当地的区域审计系统，对职能管理至关重要。因此，为了了解这些局部系统的病理生理学，特别是在心脏中，并进一步指导和优化目前可用的抗RAS治疗剂的应用，迫切需要开发非侵入性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（PET）中应用放射性标记的血管紧张素II 1型受体（AT 1）拮抗剂，RAS可用于临床评估，并为心血管疾病患者的治疗提供有价值的信息。研究科学家报告的放射性示踪剂并不理想，并且在不同水平上显示出局限性。因此，通过构效关系分析和合理的化合物设计，我们希望开发新的18F-示踪剂，从AT 1拮抗剂的临床应用。这些放射性示踪剂有望表现出与其母体药物分子相似的特异性和选择性，如缬沙坦和氯沙坦。首先生产冷化合物并用于放射性配体结合试验，以确认在AT 1和AT 2受体亚型上的相似结合和选择性。为评价靶向放射性示踪剂在体内的性质和可行性，将靶向放射性示踪剂注射到大鼠体内，评估其生物分布和代谢，并与母体化合物进行比较。此外，还将通过与参比AT 1拮抗剂竞争进行选择性阻断研究。利用小动物PET研究，上述研究将直接可视化，以进一步研究其代谢，在心脏或其他器官中的应用及其在个性化医疗中的应用潜力。

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.