Molecular Imaging of Ischemic Memory with Ultrasound - Transition to Humans

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DESCRIPTION (provided by applicant): Molecular imaging techniques with targeted imaging probes have been developed with specific clinical goals in mind. In cardiovascular disease, there is hope that molecular imaging will have a positive impact on patient management by early detection of disease or by increasing diagnostic accuracy for life-threatening illnesses. In patients who present with acute or recent chest pain but who have a non-diagnostic ECG, it may be possible to improve and expedite the diagnosis of acute coronary syndromes by imaging molecular alterations that occur with myocardial ischemia ("ischemic memory" imaging). This strategy is already being tested in clinical trials with metabolism-targeted radionuclide agents. A more rapid and portable approach would have practical advantages for evaluating these patients, most of whom are seen in the emergency department. We have developed ultrasound molecular imaging probes for detection of ischemia (with or without infarction) by targeting microbubble contrast agents to P-selectin. Ultrasound molecular imaging of P-selectin expression in murine models of brief ischemia detects the presence and extent of recent myocardial ischemia. We have recently developed an agent that is suitable for human use that is produced by conjugating a recombinant dimeric PSGL-1 analogue to microbubbles. The analogue alone is safe and is being tested in Phase-2 studies for amelioration of organ transplant injury. The purpose of this challenge grant is to transition molecular imaging technology for detection of recent ischemia into clinical trials. In preparation for this submission, arrangements have been made between our research group and a major contrast manufacturer (Bracco Imaging) for production of the agent in a GMP facility. We have four major milestones for this challenge grant proposal: (1) to test efficacy and safety of P-selectin targeted imaging in a non-human primate closed-chest model of brief myocardial ischemia; (2) to complete pharmacology/toxicology studies needed for Exploratory IND application; (3) to profile safety of the IND-approved agent in normal volunteers; and (4) to examine feasibility of imaging recent myocardial ischemia in stable patients immediately after primary percutanous intervention for acute coronary syndrome. These studies will provide necessary data for the development of a promising diagnostic approach to rapid diagnosis of patients with unstable angina and myocardial infarction, or for the detection of stress-induced ischemia in patients referred for non-invasive evaluation for coronary artery disease with stress or dobutamine echocardiography. PUBLIC HEALTH RELEVANCE: Current algorithms for the diagnosis of acute coronary syndromes (unstable angina and myocardial infarction) have major limitations leading to delayed or missed diagnosis. In this proposal, we will test the efficacy and safety of a new ultrasound targeted imaging technique that is able to detect molecular alterations in the small vessels of heart that occur during or after ischemia (low blood flow to the heart). The successful completion of our aims will lead to the development of a new strategy that can be used to more accurately diagnosis life-threatening coronary artery disease.