18F-GP1, a novel fluorine-18 labeled tracer designed for PET imaging of thrombi with high detection sensitivity and low background

Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks and pulmonary embolism are major causes of morbidity and mortality worldwide. GPIIb/IIIa is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small molecule tracer for positron emission tomography (PET) imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of 18F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood-ratio for 18F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or aorta. Results:18F-GP1 is a novel fluorine-18 labeled small molecule for PET imaging of thrombi. The IC50 of 18F-GP1 to GPIIb/IIIa was determined to be 20nM. 18F-GP1 binds to thrombi with a mean clot-to-blood ratio of 95. Binding is specific and can be displaced by excess non-radioactive derivative. Binding is not effected by anticoagulants such as aspirin or heparin. 18F-GP1 shows rapid blood clearance and a low background after i.v. injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface and small cerebral emboli were detected in vivo by PET imaging. Conclusion:18F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Due to its favorable pre-clinical characteristics, 18F-GP1 is currently being investigated in a human clinical study.