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

Abstract

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. 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 the aorta. Results:18F-GP1 is an 18F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of 18F-GP1 to GPIIb/IIIa was 20 nM. 18F-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. 18F-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. Conclusions:18F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, 18F-GP1 is currently being investigated in a human clinical study.

• Authors: Jessica Lohrke, Holger Siebeneicher, Markus Berger, Michael Reinhardt, Mathias Berndt, Andre Mueller, Marion Zerna, Norman Koglin, Felix Oden, Marcus Bauser, Matthias Friebe, Ludger M Dinkelborg, Joachim Huetter, Andrew W Stephens
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 58 Issue 7 Pg. 1094-1099 (07 2017) ISSN: 1535-5667 [Electronic] United States
• PMID: 28302764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Fluorine Radioisotopes
• Laurates
• Platelet Glycoprotein GPIIb-IIIa Complex
• Radiopharmaceuticals
• dibutyllauroylglutamide
• Glutamine

Topics

• Animals
• Female
• Fluorine Radioisotopes (chemistry, pharmacokinetics)
• Glutamine (analogs & derivatives, pharmacokinetics)
• Humans
• Isotope Labeling (methods)
• Laurates (pharmacokinetics)
• Macaca fascicularis
• Molecular Imaging (methods)
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
• Reproducibility of Results
• Sensitivity and Specificity
• Thrombosis (diagnostic imaging, metabolism)