18 F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi

Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (GPIIb/IIIa) is the key receptor involved in platelet aggregation and is a validated target for therapeutic a...

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Veröffentlicht in:Journal of Nuclear Medicine 2017-07, Vol.58 (7), p.1094-1099
Hauptverfasser: Lohrke, Jessica, Siebeneicher, Holger, Berger, Markus, Reinhardt, Michael, Berndt, Mathias, Mueller, Andre, Zerna, Marion, Koglin, Norman, Oden, Felix, Bauser, Marcus, Friebe, Matthias, Dinkelborg, Ludger M, Huetter, Joachim, Stephens, Andrew W
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Sprache:eng
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Zusammenfassung:Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (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 PET imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Binding of F-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 F-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 the aorta. F-GP1 is an F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of F-GP1 to GPIIb/IIIa was 20 nM. F-GP1 bound to thrombi with a mean clot-to-blood ratio of 95. Binding was specific and can be displaced by excess nonradioactive derivative. Binding was not affected by anticoagulants such as aspirin or heparin. F-GP1 showed rapid blood clearance and a low background after intravenous 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. F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, F-GP1 is currently being investigated in a human clinical study.
ISSN:0161-5505
1535-5667
2159-662X
DOI:10.2967/jnumed.116.188896