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

J Nucl Med. 2017 Jul;58(7):1094-1099. doi: 10.2967/jnumed.116.188896. Epub 2017 Mar 16.

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.

Keywords: embolism; glycoproteins; imaging; platelets; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Fluorine Radioisotopes / chemistry
  • Fluorine Radioisotopes / pharmacokinetics
  • Glutamine / analogs & derivatives*
  • Glutamine / 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
  • Radiopharmaceuticals / pharmacokinetics
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Thrombosis / diagnostic imaging*
  • Thrombosis / metabolism*

Substances

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