[18F]GP1, a novel fluorine-18 labeled tracer for PET imaging of thrombi

331 Objectives Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks (TIA) and pulmonary embolism are major causes of morbidity and mortality worldwide. GPIIb/IIIa is the key receptor involved in platelet aggregation and is an excellent target for platelet imaging. A specific fluorine-18 labeled tracer with high affinity to GPIIb/IIIa could improve the detection of thrombi by overcoming the limitations of previous introduced SPECT (99mTc) tracers. Methods [18F]GP1 is a novel fluorine-18 labeled small molecule, synthesized by nucleophilic fluorination of the corresponding tosylate precursor. The binding affinity to GPIIb/IIIa was determined in a competition assay using immobilized human receptor. The blood-to-clot-ratio for [18F]GP1 was investigated by an in vitro blood flow model using blood from various species. Small thrombus depositions on catheter surfaces were detected by PET imaging after insertion of a roughened catheter into either the vena cava or aorta of cynomolgus monkeys. Results [18F]GP1 binds with high affinity (IC50 = 20 nM) to GPIIb/IIIa receptors on the surface of activated platelets. Binding of [18F]GP1 was further confirmed by autoradiography using a cardiac thrombus from an explanted human heart. In the in vitro human blood flow model, [18F]GP1 binds stably to thrombi with a clot-to-blood ratio between 71 and 95. Binding can be displaced by an excess of the non-radioactive compound. A high clot-to-blood-ratio was also observed for cynomolgus, but not for pig, dog and rabbit, blood. In vivo imaging studies in non-human primates revealed significant accumulation of [18F]GP1 on arterial as well as on venous thrombi with a low background. Conclusions [18F]GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Due to the excellent pre-clinical characteristics [18F]GP1 is currently further investigated in a human Proof-of-Mechanism-Study.