PET Imaging of Thrombus

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.

Grant Number: 5R01HL109448-12
NIH Institute/Center: NIH
Principal Investigator: Peter Caravan