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 positron emission tomography probe 64Cu-FBP8. Here, we tested the feasibility of 64Cu-FBP8-PET to detect source thrombi and culprit emboli after deep vein thrombosis and pulmonary embolism (DVT-PE). To support clinical translation of 64Cu-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 days after deep vein thrombosis by intrajugular injection of a preformed blood clot labeled with 125I-Fibrinogen. PET imaging was performed to detect the clots, and single-photon emission tomography (SPECT) was used to confirm in vivo the location of the pulmonary emboli. Ex vivo gamma-counting and histopathology were used to validate the imaging findings. Detailed biodistribution was performed in healthy rats (n=30) at different time-points after 64Cu-FBP8 administration to estimate human radiation dosimetry. Longitudinal whole-body PET/MR imaging (n=2) was performed after 64Cu-FBP8 administration to further assess radioactivity clearance. Results 64Cu-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 gamma-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 rapid, primarily renal, body clearance of 64Cu-FBP8. The effective dose was estimated to be 0.021 mSv/MBq for male and 0.027 mSv/MBq for female, supporting the feasibility of using 64Cu-FBP8 in human trials. Conclusions We showed that 64Cu-FBP8-PET is a feasible approach to image DVT-PE, and that radiogenic adverse health effects should not limit the clinical translation of 64Cu-FBP8.

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of 111In- and 68Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

“…Nevertheless, the relatively high clot uptake, combined with the lower kidney retention, suggest that these probes are still promising for clinical applications. 64 Cu-FBP8 was recently reported to have favorable dosimetry properties for human translation, (24) and this should be true of 68 Ga-FBP14 as well owing to the shorter half-life of 68 Ga compared to 64 Cu.…”

Multisite Thrombus Imaging and Fibrin Content Estimation With a Single Whole-Body PET Scan in Rats

“…However, the high sensitivity of PET allows using micrograms of tracer compared to other contrast-based imaging modalities where grams of probe are required (e.g., MRI), thus reducing potential chemical toxicity. Despite the relatively long half-life of 64 Cu (12.7 h), the rapid whole-body clearance and low retention of 64 Cu-FBP8 suggest that radiogenic adverse effects should not limit its clinical translation 18 , and recent radiation dosimetry studies in rats support this conclusion 38 . Moreover, the longer half-life may allow synthesis of the molecular probe in advance, and even on demand shipment to remote sites far from a cyclotron.…”

18F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi

“…It received Food and Drug Administration approval for this indication but was later abandoned. 99m Tc-Fab against D-Dimer progressed to phase 2 (20,21), and preclinical studies with 64 Cu-labeled peptides binding to fibrin have recently been described (22). The main limitations of agents previously investigated in the clinic were low target-to-background ratios, slow clearance, and inability to distinguish acute versus chronic disease (18).…”