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

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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.