Labeled inhibitors for angiotensin converting enzyme

描述（由申请人提供）： 尽管缺血性心脏病和中风导致的死亡率呈下降趋势，但美国充血性心力衰竭的患病率及其导致的死亡率在过去三十年中几乎增加了两倍。充血性心力衰竭仍然是美国和欧洲的主要死亡原因（Levy 2002，Cowie 1999）。据估计，在未来二十年内，冠状动脉疾病引起的心力衰竭将超过所有传染病，成为世界上主要的死亡原因（Murray 1996）。心力衰竭的发病率和死亡率较低;临床衰竭和左心室功能障碍越严重，预后越差。使用血管紧张素转换酶（ACE）抑制剂的大型临床试验已证明可降低有充血性心力衰竭症状的冠状动脉疾病和左心室功能不全患者的发病率和死亡率风险。ACE抑制剂现在是治疗心力衰竭、心肌梗死后心室扩张和重塑、内皮功能障碍和糖尿病肾病患者的中心。该基金的目标是开发一系列ACE放射性示踪剂，通过外部成像监测ACE活性作为进行性心力衰竭的功能。将使用单光子发射断层扫描（SPECT）和正电子发射断层扫描（PET）放射性示踪剂。组织特异性ACE放射性配体的开发将代表首次使用外部成像对患有慢性缺血性心肌病和心力衰竭的人类心脏进行ACE研究。该项目的临床意义，如果成功的话，将是更好地定义复杂的生化现象，目前被描述为心力衰竭和心脏重塑。此外，如果ACE增加的发现是可逆的，即使用ACE抑制剂，则PET的无创成像将允许在胶原蛋白替代疗法之前监测此类患者的疾病进展以及药物和介入治疗的效果。影像学技术，可以识别增加ACE的患者，前瞻性的，在过渡到替代纤维化和重塑发生之前，可能会导致保留左心室功能，从而改善整体预后。

DESCRIPTION (provided by applicant): Despite the trend of decreasing death rates attributable to ischemic heart disease and stroke, the prevalence of congestive heart failure and the resultant death rates in the United States have almost tripled over the past three decades. Congestive heart failure remains a leading cause of death in United States and Europe (Levy 2002, Cowie 1999). It is estimated that over the next two decades, heart failure due to coronary artery disease will surpass all infectious diseases to become the leading cause of death in the world (Murray 1996). Heart failure is associated with poor morbidity and mortality; the more severe the clinical failure and left ventricular dysfunction, the worse the prognosis. Large clinical trials using angiotensin-converting enzyme (ACE) inhibitors have proven to reduce the risk of morbidity and mortality in patients with coronary artery disease and left ventricular dysfunction who have symptoms of congestive heart failure. ACE inhibition is now central to the treatment of patients with heart failure, ventricular dilatation and remodeling after myocardial infarction, endothelial dysfunction, and diabetic nephropathy. The goal of this grant is to develop a series of radiotracers for the ACE that can monitor ACE activity as a function of progressive heart failure by external imaging. Both single photon emission tomography (SPECT) and positron emission tomography (PET) radiotracers will be used. The development of a tissue specific ACE radioligand will represent the first study of ACE in human hearts with chronic ischemic cardiomyopathy and heart failure using external imaging. The clinical significance of this project, if successful, will be to better define the complex biochemical phenomena presently described as heart failure and cardiac remodeling. Moreover, if the finding of increased ACE is reversible i.e. with ACE inhibitors, noninvasive imaging with PET would allow monitoring of both the progression of disease and the effect of medical and interventional therapies in such patients before collagen replacement ensues. Imaging techniques that can identify patients with increased ACE, prospectively, before the transition to replacement fibrosis and remodeling occurs, may result in preserved left ventricular function thereby improving overall prognosis.