title: Radiation Dosimetry of the Fibrin-Binding Probe ⁶⁴Cu-FBP8 and Its Feasibility for PET Imaging of Deep Vein Thrombosis and Pulmonary Embolism in Rats.
abstract: The diagnosis of deep venous thromboembolic disease is still challenging despite the progress of current thrombus imaging modalities and new diagnostic algorithms. We recently reported the high target uptake and thrombus imaging efficacy of the novel fibrin-specific PET probe (64)Cu-FBP8. Here, we tested the feasibility of (64)Cu-FBP8 PET to detect source thrombi and culprit emboli after deep vein thrombosis and pulmonary embolism (DVT-PE). To support clinical translation of (64)Cu-FBP8, we performed a human dosimetry estimation using time-dependent biodistribution in rats.
  
  
  METHODS
  Sprague-Dawley rats (n = 7) underwent ferric chloride application on the femoral vein to trigger thrombosis. Pulmonary embolism was induced 30 min or 2 d after DVT by intrajugular injection of a preformed blood clot labeled with (125)I-fibrinogen. PET imaging was performed to detect the clots, and SPECT was used to confirm in vivo the location of the pulmonary emboli. Ex vivo γ counting and histopathology were used to validate the imaging findings. Detailed biodistribution was performed in healthy rats (n = 30) at different time points after (64)Cu-FBP8 administration to estimate human radiation dosimetry. Longitudinal whole-body PET/MR imaging (n = 2) was performed after (64)Cu-FBP8 administration to further assess radioactivity clearance.
  
  
  RESULTS
  (64)Cu-FBP8 PET imaging detected the location of lung emboli and venous thrombi after DVT-PE, revealing significant differences in uptake between target and background tissues (P < 0.001). In vivo SPECT imaging and ex vivo γ counting confirmed the location of the lung emboli. PET quantification of the venous thrombi revealed that probe uptake was greater in younger clots than in older ones, a result confirmed by ex vivo analyses (P < 0.001). Histopathology revealed an age-dependent reduction of thrombus fibrin content (P = 0.006), further supporting the imaging findings. Biodistribution and whole-body PET/MR imaging showed a rapid, primarily renal, body clearance of (64)Cu-FBP8. The effective dose was 0.021 mSv/MBq for males and 0.027 mSv/MBq for females, supporting the feasibility of using (64)Cu-FBP8 in human trials.
  
  
  CONCLUSIONS
  We showed that (64)Cu-FBP8 PET is a feasible approach to image DVT-PE and that radiogenic adverse health effects should not limit the clinical translation of (64)Cu-FBP8.
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Oliveira
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Rietz
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Rotile
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Helen
authors.initials: H
authors.lastname: Day
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Pratap C
authors.initials: PC
authors.lastname: Naha
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: David P
authors.initials: DP
authors.lastname: Cormode
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Izquierdo-Garcia
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Ciprian
authors.initials: C
authors.lastname: Catana
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, Massachusetts caravan@nmr.mgh.harvard.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
mesh_terms: D000465:Algorithms; D000818:Animals; D003301:Copper Radioisotopes / Q000737:chemistry*; D005260:Female; D005337:Fibrin / Q000737:chemistry*; D008297:Male; D049268:Positron-Emission Tomography; D011655:Pulmonary Embolism / Q000000981:diagnostic imaging*; D011874:Radiometry / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000000981:diagnostic imaging; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D020246:Venous Thrombosis / Q000000981:diagnostic imaging*; D051598:Whole Body Imaging
chemical_list: D003301:Copper Radioisotopes; D005337:Fibrin
keywords: DVT-PE; PET imaging; dosimetry; fibrin; thrombosis