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

用于心脏血管紧张素 II 1 型受体成像的新型 18F-PET 示踪剂的开发和评估

基本信息

批准号：
326751428
负责人：
Dr. Xinyu Chen
金额：
--
依托单位：
Klinik und Poliklinik für Nuklearmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/326751428?language=en
关键词：
Development Evaluation Novel 18F PET

项目摘要

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.

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着重要作用。这些器官中存在局部ras，对功能调节至关重要。因此，为了了解这些局部系统，特别是心脏中的这些系统的病理生理，并进一步指导和优化现有抗ras治疗药物的应用，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）中应用放射性标记血管紧张素II型1受体（AT1）拮抗剂，可以在临床上评估RAS，并为心血管疾病患者的治疗提供有价值的信息。科学家研究报告的放射性示踪剂并不理想，在不同的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，我们希望从AT1拮抗剂衍生出临床应用的新型18f示踪剂。这些放射性示踪剂有望表现出与其母体药物分子（如缬沙坦和氯沙坦）相似的特异性和选择性。这些示踪剂的前体将被合成和表征。冷化合物将首先生产并用于放射性配体结合试验，以确认AT1和AT2受体亚型的相似结合和选择性。然后应用相关程序获得目标18f标记的示踪剂。为了评估目标示踪剂的体内性能和可行性，将其注射到大鼠体内；将评估其生物分布和代谢，并与母体化合物进行比较。此外，与参考AT1拮抗剂竞争的选择性阻断研究也将进行。利用小动物PET研究，将上述研究直接可视化，进一步研究其代谢、在心脏或其他器官中的应用以及在个性化医疗中的应用潜力。