Molecular Imaging of Venous Thrombosis with new Specific PET Radiopharmaceuticals – ThromPET

Rational: Venous thromboembolism (VTE), clinically presenting as deep vein thrombosis (DVT) or pulmonary embolism (PE), is the third most frequent acute cardiovascular disease after myocardial infarction and stroke, and is associated with high mortality (around 10%). The frequency and the severity of VTE have not changed over the past 20 years despite major advances in diagnostic tests and therapeutic improvement. Particularly, distinguishing recurrent VTE from residual clot is of foremost importance. Indeed, therapeutic implications differ significantly whether the patient is facing an acute VTE versus a relatively passive residual thrombus whereas it remains challenging with the current imaging modalities to have a definite diagnosis. In deed, current imaging techniques although well validated for the exclusion of VTE at the acute phase, do not provide any information about the composition of the thrombus and can not distinguish between residual and newly formed clots.
Molecular imaging has emerged at the end of the last century as a new in vivo imaging method allowing the visualization, characterization, and measurement of biological processes at a cellular or molecular level. In the setting of VTE, molecular imaging allows noninvasive direct targeting of the thrombus with high specificity and sensitivity with a potential of whole-body imaging. Targeting directly the active venous clot may allow a direct visualization of a specific part of the thrombus. Many studies since the end of the 1970s have already investigated the role of molecular imaging for the diagnosis of VTE targeting various contributors of thrombosis, as well as the different components of the venous clot. However, studies were performed using conventional planar or single photon emission computed tomography (SPECT) imaging, resulting in insufficient spatial resolution and detectability.
Nuclear medicine and molecular imaging have undergone a technologic revolution with the development of an increasing array of new positron emission tomography (PET) tracers. Technical advantages of PET compared to SPECT include higher sensitivity, higher spatial resolution (4 mm for PET vs. 12 mm for SPECT), and superior quantitative capability.
Objectives: The objective of this project is to develop new radiotracers for VTE diagnosis using PET technology, derived from tracers already assessed in humans with SPECT technology and to test them in pre-clinical models of thrombosis.
Research hypotheses and methodology: We have selected three biomolecules corresponding to different constituents and steps of thrombus formation, that may potentially distinguish fresh (i.e recurrent VTE) from old thrombi (i.e residual clot), which is of foremost importance for clinicians. The challenge of this project is to find the appropriate combination of [targeting biomolecule/radionuclide with the suitable half-life/corresponding radioisotope-chelating agent] for a safe use and to propose the relevant biological and radiopharmaceutical approach from in vitro to in vivo studies.The three radiotracers will be produced by combining selected biomolecules targeting early and late thrombotic processes, and labeled with 64-copper (WP1). The binding capacity of synthetized radiopharmaceuticals to venous clots will be evaluated using ex vivo models of thrombus formation (WP2). Biodistribution, pharmacokinetic and binding capacity of synthetized radiopharmaceuticals to a clot will be evaluated in a mouse model of venous thrombosis (WP3).
Expected results: We expect to improve the sensitivity of existing tracers using PET technology that will greatly facilitate their translation into humans, leading to the development of the world’s first PET radiopharmaceutical dedicated to recurrent VTE diagnosis with high specificity and sensitivity that could strongly modify patient care.