GMP-Compliant Radiosynthesis of [18F]GP1, a Novel PET Tracer for the Detection of Thrombi

Abstract

Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [18F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific 18F-labeled small-molecule radiotracer that binds with high affinity to GPIIb/IIIa receptors of activated platelets. An improved, robust and fully automated radiosynthesis of [18F]GP1 has been developed. [18F]GP1 has been synthesized with decay corrected radiochemical yields of 38 ± 6%, with a radiochemical concentration up to 1900 MBq/mL, molar activities of 952–9428 GBq/µmol and a radio-chemical purity >98%. After determination of the optimal reaction conditions, in particular for HPLC separation, adaption of the reaction conditions to PET center requirements, validation of the manufacturing process and the quality control methods, the synthesis of [18F]GP1 was successfully implemented to GMP standards and was available for clinical application. We describe the GMP-compliant synthesis of the novel radiotracer [18F]GP1. Moreover, we provide some proof-of-concept examples for clinical application in the cardiovascular field. PET/CT with the novel small-molecular radiotracer [18F]GP1 may serve as a novel highly sensitive tool for visualizing active platelet aggregation at the molecular level.

Molecular Imaging of Lower Extremity Peripheral Arterial Disease: An Emerging Field in Nuclear Medicine

“…Specifically, advancements with cadmium zinc telluride (CZT) SPECT systems and whole-body PET cameras may offer new approaches for quantifying absolute perfusion of lower extremity skeletal muscle beyond what has been previously accomplished with conventional 15 O-water PET imaging. Expanded application of 18 F-FDG and 18 F-NaF to the lower extremities, along with other developing radionuclides meant for atherosclerosis and thrombosis targeted imaging, could also allow for novel opportunities to investigate mechanisms associated with PAD disease progression and non-invasively detect occlusive peripheral thrombi (49)(50)(51)(52)(53). Additionally, the use of multi-tracer imaging of different physiological processes in the lower extremities could theoretically be achieved with SPECT imaging of radionuclides that possess distinctly different gamma ray energy photopeaks, or with PET imaging by staggering injection times of short half-life radionuclides; however, the advantages and disadvantages associated with increased radiation exposure for patients receiving multiple radionuclide injections in a single imaging session would need to be carefully considered.…”

Radiotracers to Address Unmet Clinical Needs in Cardiovascular Imaging, Part 2: Inflammation, Fibrosis, Thrombosis, Calcification, and Amyloidosis Imaging

“…The binding of 18 F-GP1 to glycoprotein IIb/ IIIa is highly specific and appears to be minimally affected by aspirin or heparin treatment (55). In preliminary clinical evaluations, 18 F-GP1 demonstrated the ability to identify thrombotic lesions in patients with acute deep venous thrombosis or pulmonary embolism ( 53), acute arterial thrombi (54), bioprosthetic valve thrombi (56), left atrial appendage thrombi (56), jugular vein thrombi (56), and left ventricular assist device thrombi (Fig. 4) (56).…”

“…In preliminary clinical evaluations, 18 F-GP1 demonstrated the ability to identify thrombotic lesions in patients with acute deep venous thrombosis or pulmonary embolism ( 53), acute arterial thrombi (54), bioprosthetic valve thrombi (56), left atrial appendage thrombi (56), jugular vein thrombi (56), and left ventricular assist device thrombi (Fig. 4) (56). However, 18 F-GP1's vessel-level detection rate of pulmonary embolism was significantly lower than that for deep venous thrombosis (60% vs. 89%, P , 0.001), a finding that may relate to lower levels of activated platelets in older, embolic thrombi or inhibition of platelet activation in the setting of large pulmonary embolism (53).…”