Proteolytic Imaging of Remodeling Myocardium

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 DESCRIPTION (provided by applicant): Proteolytic Imaging of Remodeling Myocardium Abstract Heart attacks (i.e. myocardial infarction or MI) occur in more than 1.2 million patients annually. Advances in interventional and pharmacological therapies have dramatically improved survival following the initial MI, and patients are often surviving acute MI with more extensive myocardial injury. Consequently, the number of patients with previous MI continues to increase and as a result put in jeopardy millions of patients for development of heart failure an adverse outcome associated with extensive myocardial injury post-MI. In these patients with a previous MI, despite optimal standard-of-care, a scar can form in the portion of the heart muscle (myocardium) that was injured from the MI. Formation of a myocardial scar following MI is associated with a malignant remodeling process with respect to changes in the structure and shape of the MI region (infarct expansion), which is due to activation of enzymes that degrade key structures of the MI region - termed matrix metalloproteinases (MMPs). This adverse remodeling after MI can lead to increased morbidity and mortality in these patients. The development of new pharmacological / therapeutic approaches to target this process has been hampered by our ability to visualize and measure MMP activity in the heart of patients post-MI. The technology to be advanced in this application directly addresses this unmet medical need by developing a unique MMP targeted imaging agent that can be used in the clinical context of post-MI remodeling in patients, and thus move the entire field forward in terms of risk stratification and the evaluation of new therapies. This fast track technology transfer application is intended to move forward the MMP imaging technology by finalizing the formulation and validation of this approach in a clinically relevant preclinical large animal model of MI and then perform first in man safety and preliminary proof of concept studies. These studies will be undertaken in two phases. Phase I: standardize the synthesis and formulation of the radiolabeled MMP targeted imaging agent and perform initial toxicity studies in rodents. Phase II: perform in vivo serial MMP imaging and validate quantitative image analysis tools in an established preclinical large animal model of post-MI remodeling. Perform initial safety, biodistribution, and dosimetry studies in normal volunteers, and preliminary feasibility and proof of concept studies in patients post-MI through an Exploratory IND pathway, demonstrating that this technology would be highly relevant to identifying patients at increased risk for heart failur and as a companion diagnostic for the purposes of testing new drugs for reducing adverse post- MI remodeling.