PET Imaging of Thrombus

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Project Summary Stroke is the second leading cause of mortality worldwide, and ischemic stroke represents 85% of strokes in the United States. A key step in the management of stroke is the identification of its cause, which has profound therapeutic and prognostic implications. For ischemic (embolic) stroke, identifying the source of the embolus allows informed treatment decisions to be made to prevent recurrent stroke. Despite the importance of identifying the etiology of stroke, some 30-40% of ischemic strokes are “cryptogenic,” where the source of the thromboembolism is never identified. Underlying sources of cryptogenic stroke include undetected atrial fibrillation/intracardiac thrombi, atheroma of the aortic arch, atherosclerosis of the carotid or vertebral arteries, and paradoxical embolism of deep venous thrombosis across a patent foramen ovale. Currently identifying the source of stroke involves multiple imaging studies including transesophageal echocardiography (TEE), magnetic resonance imaging, computed tomography and duplex ultrasound, and is frequently negative. In addition, these techniques rely of the presence of echogenic material or filling defects to detect thrombus, which provides no biological information at all on the thrombus. To address these limitations we have developed the fibrin-binding PET probe 64Cu-FBP8. In the previous cycles of this award, we invented this probe and validated it preclinically in rodent models of arterial, venous, and embolic thrombosis. We next performed IND enabling preclinical safety and manufacturing studies, and obtained an IND from FDA to translate 64Cu-FBP8 to clinical research. Imaging in healthy volunteers established favorable dosimetry, rapid renal clearance, and low background signal in the head, neck, thorax, and deep veins. In 24 patients with atrial fibrillation, 64Cu-FBP8 PET was 100% sensitive and 84% specific for the detection of left atrial appendage (LAA) thrombus, using TEE as the gold standard. Having validated the accuracy of 64Cu-FBP8 for the detection of LAA thrombus in stable outpatients, we now seek to expand the use of the probe to detect thrombus in acutely ill hospitalized patients and, specifically, patients with acute stroke. The aim of this renewal is to use PET-CT of 64Cu-FBP8 to detect the source of embolus in ischemic stroke and in particular cryptogenic stroke. Multi-station PET imaging of 64Cu-FBP8 will provide a whole-body readout of thrombus burden and will allow important questions in stroke pathogenesis to be addressed. In addition, the signature from 64Cu-FBP8 will provide an index of thrombus age, allowing the impact of this on embolism to be determined. In aim 1 of the proposal we will validate the ability of PET-CT of 64Cu-FBP8 to detect thrombus in hospitalized patients. In aim 2 we will use the agent in subjects with acute stroke of known origin, and in aim 3 we will study subjects with cryptogenic stroke. Execution of the study will provide important insights and lay the foundation for the use of 64Cu-FBP8 in the prevention and management of stroke.