Investigation of ANG II/AT1 Receptors with PET

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DESCRIPTION (provided by applicant): During the previous funding period of this grant, several radioligands were synthesized for positron emission tomography (PET) imaging of the angiotensin II/subtype 1 receptor (AT1R). The effects of dietary sodium, estrogen, various drugs and arterial stenosis on radioligand binding in the kidneys were investigated. The results of these experiments reinforced the soundness of positron emission tomography (PET) as a state-of-the-art noninvasive imaging technique for studying the regulation of renal AT1R in vivo. Although the ultimate goal is to apply this molecular imaging tool in humans, kinetic properties of the radioligands need first be clarified in animal models. Our initial observations in dogs and pigs showed increased binding of the radioligand in renal artery stenosis. The important task remaining is to understand and quantify the distribution and kinetics of the PET radioligand in response to altered renal blood flow. To accomplish this, PET studies are proposed in dogs with and without reduced perfusion of the kidneys. The following specific aims will be addressed: Aim 1: To determine to what degree radioligand binding parameters obtained with PET studies are affected by renal blood flow. Experiments are proposed to test the hypothesis that increased in vivo radioligand binding observed in vivo correlates with in vitro quantification of the receptor in Goldblatt models of renal hypoperfusion. We also postulate that after restoration of blood flow radioligand binding will return to pre-ischemic levels. Aim 2: To apply novel quantitative PET image reconstruction and post-processing algorithms for improved receptor quantification in vivo. This aim will address the hypothesis that computational compensation for image degradation and radioligand delivery can provide receptor binding parameters largely independent of global and regional variations of organ perfusion. Integration of the preclinical experiments and the novel computational algorithms will facilitate translation of renal molecular imaging into clinical practice and lead to a rational approach for molecular diagnosis of renovascular disease. PUBLIC HEALTH RELEVANCE Kidney disease remains an important public health problem since it is closely linked to obesity, metabolic syndrome, diabetes, atherosclerosis and hypertension. The imaging techniques currently used to evaluate involvement of the kidneys rely on anatomical data. In contrast, positron emission tomography imaging (PET) makes it possible to study diseases at the molecular level. The proposed research is designed to establish PET imaging of the angiotensin receptor. In the future, this new molecular imaging tool is expected to diagnose kidney disease sooner, guide therapy, measure therapy response and detect disease recurrence or deterioration at an earlier stage.