PET Imaging of Thrombus

Summary

Principal Investigator: PETER D CARAVAN
Abstract: DESCRIPTION (provided by applicant): Positron Emission Tomography Imaging of Thrombus. The goal of this proposal is to develop a fibrin-specific positron emission tomography (PET) probe for direct imaging of thrombus. Thrombus is implicated in a range of pathologies, e.g. ischemic stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. The presence of thrombus changes treatment decisions and imaging is widely used rule in, or out, the presence of thrombus. Despite the different imaging methods available, there is still a strong unmet medical need for direct identification of thrombus. For instance, identification of the source of the embolus in ischemic stroke is critical to patient management, but currently 30- 40% of strokes are of unknown origin. This proposed PET probe may enable identification of stroke source and identify patients who would benefit from more aggressive antithrombotic therapy to prevent secondary stroke. Stroke is the third leading cause of death and the leading cause of morbidity in the US. According to the American Stroke Association, Americans will pay almost $69 billion dollars this year in stroke related medical costs and disability. An imaging tool to identify those at risk for secondary stroke may be expected to positively impact morbidity and mortality associated with stroke. The thrombus probe is based on a peptide that binds to and has specificity for fibrin over circulating fibrinogen or other plasma proteins. Fibrin is present in acute and sub-chronic venous and arterial thrombi in high concentrations, but fibrin is not present in circulating blood. A selective fibrin imaging probe is expected to provide high sensitivity and specificity for thrombus identification. While PET offers molecular specificity, it suffers from low spatial resolution and lacks anatomical landmarks. Hybrid PET - computed tomography (CT) or PET - magnetic resonance imaging (MRI) devices are now available that enable co-registration of the molecular PET image to the vascular anatomical images obtained by CT or MRI. This proposal builds on positive preliminary PET-MRI thrombus imaging data with a prototype PET probe. In Aim 1 we focus on synthesizing a series of fluorine-18 and copper-64 labeled peptides to optimize the imaging properties of thrombus-targeted PET probe. In Aim 2 we will characterize these new probes with respect to their affinity to the fibrin target, their specificity for fibrin over other plasma proteins, and their metabolic stability in the presence of plasma or liver homogenate. In Aim 3 we explore the efficacy of these probes in fresh and aged thrombus models in rats and rabbits using PET-CT and PET-MRI. Dosimetry estimates will be performed on optimized probes and the most promising will be evaluated for acute toxicity. The output of this research will be a novel thrombus imaging probe that may be subsequently developed for human use.
Funding Period: 2011-08-01 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Discrete bimodal probes for thrombus imaging
    Ritika Uppal
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Suite 2301, Charlestown, Massachusetts 02129, USA
    J Am Chem Soc 134:10799-802. 2012
  2. ncbi Science to practice: how will myocardial inflammation be imaged with MR imaging?
    David E Sosnovik
    Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Radiology 264:309-11. 2012
  3. pmc Molecular imaging of fibrin in a breast cancer xenograft mouse model
    Ritika Uppal
    Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    Invest Radiol 47:553-8. 2012
  4. pmc Fibrin-targeted PET probes for the detection of thrombi
    Katie L Ciesienski
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, USA
    Mol Pharm 10:1100-10. 2013
  5. pmc Pycup--a bifunctional, cage-like ligand for (64)Cu radiolabeling
    Eszter Boros
    The Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States
    Mol Pharm 11:617-29. 2014
  6. pmc Activation and retention: a magnetic resonance probe for the detection of acute thrombosis
    Galen S Loving
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, MA 02129 USA
    Angew Chem Int Ed Engl 53:1140-3. 2014
  7. pmc In vivo molecular imaging of thrombosis and thrombolysis using a fibrin-binding positron emission tomographic probe
    Ilknur Ay
    From the Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
    Circ Cardiovasc Imaging 7:697-705. 2014

Detail Information

Publications8

  1. pmc Discrete bimodal probes for thrombus imaging
    Ritika Uppal
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Suite 2301, Charlestown, Massachusetts 02129, USA
    J Am Chem Soc 134:10799-802. 2012
    ..Imaging studies showed that these probes could detect fibrin over a wide range of probe concentrations by optical, magnetic resonance, and positron emission tomography imaging...
  2. ncbi Science to practice: how will myocardial inflammation be imaged with MR imaging?
    David E Sosnovik
    Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Radiology 264:309-11. 2012
    ..The approach described by Naresh et al adds a valuable tool to the preclinical molecular imaging armamentarium...
  3. pmc Molecular imaging of fibrin in a breast cancer xenograft mouse model
    Ritika Uppal
    Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    Invest Radiol 47:553-8. 2012
    ..Fibrin deposition has been indicated within the stroma of a majority of solid tumors. Here we assess the feasibility of using the established fibrin-specific probe EP-2104R for noninvasive imaging of fibrin in the context of breast cancer...
  4. pmc Fibrin-targeted PET probes for the detection of thrombi
    Katie L Ciesienski
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, USA
    Mol Pharm 10:1100-10. 2013
    ..FBP1 and FBP2 represent promising new probes for the molecular imaging of thrombi...
  5. pmc Pycup--a bifunctional, cage-like ligand for (64)Cu radiolabeling
    Eszter Boros
    The Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States
    Mol Pharm 11:617-29. 2014
    ..Pycup2A was readily conjugated to a fibrin-targeted peptide and labeled with (64)Cu for successful PET imaging of arterial thrombosis in a rat model, demonstrating the utility of our new chelator in vivo. ..
  6. pmc Activation and retention: a magnetic resonance probe for the detection of acute thrombosis
    Galen S Loving
    A A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, MA 02129 USA
    Angew Chem Int Ed Engl 53:1140-3. 2014
    ..To address this need, an activatable magnetic resonance (MR) probe that is responsive to a key biochemical process associated with recently formed clots has been developed. ..
  7. pmc In vivo molecular imaging of thrombosis and thrombolysis using a fibrin-binding positron emission tomographic probe
    Ilknur Ay
    From the Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
    Circ Cardiovasc Imaging 7:697-705. 2014
    ..Here, we describe imaging properties and target uptake of a new fibrin-specific positron emission tomographic probe for thrombus detection and therapy monitoring in 2 rat thrombosis models...

Research Grants30

  1. Therapeutic Protein C Activator for Myocardial Ischemia
    NORAH VERBOUT; Fiscal Year: 2013
    ..Reaching our milestones will prompt the initiation of formal product development towards an IND for the emergency treatment of suspected and/or verified myocardial ischemia. ..
  2. Novel Methods for Dissolving Blood Clots
    GUY LELAND REED; Fiscal Year: 2013
    ..Upon completion of this Phase II project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to heart and stroke victims. ..
  3. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  4. Reducing Stroke by a Novel, Clot-dissolving Antibody
    GUY LELAND REED; Fiscal Year: 2013
    ....
  5. NOVEL PET AGENT FOR MYOCARDIAL PERFUSION IMAGING
    Vijay Sharma; Fiscal Year: 2013
    ..Successful execution of the outlined objectives should provide a molecular-targeted 68Ga-PET agent for MPI and management of CAD. ..