title: 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 of18F-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 for18F-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 an18F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of18F-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.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lohrke
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Holger
authors.initials: H
authors.lastname: Siebeneicher
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Reinhardt
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Berndt
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Zerna
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Koglin
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Oden
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bauser
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
authors.affiliation: Bayer AG, Drug Discovery, Berlin, Germany; and.
authors.forename: Joachim
authors.initials: J
authors.lastname: Huetter
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany andrew.stephens@piramal.com.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stephens
mesh_terms: D000818:Animals; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005973:Glutamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D007848:Laurates / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D057054:Molecular Imaging / Q000379:methods*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013927:Thrombosis / Q000000981:diagnostic imaging* / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D007848:Laurates; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019275:Radiopharmaceuticals; C514084:dibutyllauroylglutamide; D005973:Glutamine
keywords: embolism; glycoproteins; imaging; platelets; thrombosis