Labeled inhibitors for angiotensin converting enzyme

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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.