Investigation of ANG II/AT1 Receptors with PET

描述(申请人提供)：在这笔赠款的前一次资助期间，合成了几个放射性配基，用于血管紧张素II/亚型1受体(AT1R)的正电子发射断层扫描(PET)成像。研究了膳食钠、雌激素、各种药物和动脉狭窄对肾脏放射性配基结合的影响。这些实验结果加强了正电子发射断层扫描(PET)作为一种最先进的非侵入性成像技术在体内研究肾脏AT1R调节的可靠性。虽然最终目标是将这种分子成像工具应用于人类，但放射性配体的动力学性质需要首先在动物模型中得到澄清。我们最初在狗和猪身上的观察显示，肾动脉狭窄时放射性配基的结合增加。剩下的重要任务是了解和量化PET放射性配基的分布和动力学，以响应肾血流的变化。为了实现这一点，建议对肾脏灌注量减少和不减少的狗进行PET研究。具体目标如下：目标1：确定PET研究获得的放射性配基结合参数受肾血流影响的程度。实验被用来检验这样的假设，即体内观察到的放射性配基结合增加与肾脏低灌流Goldblatt模型中受体的体外定量相关。我们还假设，血流恢复后，放射性配基结合将恢复到缺血前的水平。目的：应用新的PET图像定量重建和后处理算法来改进体内受体的定量。这一目标将解决这样一个假设，即对图像退化和放射性配基传递的计算补偿可以提供在很大程度上独立于器官灌注的全球和区域差异的受体结合参数。临床前实验和新的计算算法的结合将有助于将肾脏分子成像转化为临床实践，并为肾血管疾病的分子诊断提供一种合理的方法。肾脏疾病仍然是一个重要的公共卫生问题，因为它与肥胖、代谢综合征、糖尿病、动脉粥样硬化和高血压密切相关。目前用于评估肾脏受累的成像技术依赖于解剖学数据。相比之下，正电子发射断层成像(PET)使在分子水平上研究疾病成为可能。这项拟议的研究旨在建立血管紧张素受体的PET成像。在未来，这种新的分子成像工具有望更早地诊断肾脏疾病，指导治疗，测量治疗反应，并在早期阶段检测疾病的复发或恶化。

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.