Dataset Information

Dosimetry of [⁶⁴Cu]FBP8: a fibrin-binding PET probe.

ABSTRACT:

Purpose

This study presents the biodistribution, clearance and dosimetry estimates of [⁶⁴Cu]Fibrin Binding Probe #8 ([⁶⁴Cu]FBP8) in healthy subjects.

Procedures

This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [⁶⁴Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 hours, 4h and 24h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software.

Results

Subjects were injected with ~400 MBq of [⁶⁴Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [⁶⁴Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67 min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG, 0.020mSv/MBq).

Conclusions

This study demonstrates the following properties of the [⁶⁴Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20 minutes in a single session. These properties provide the basis for [⁶⁴Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions.

SUBMITTER: Izquierdo-Garcia D

PROVIDER: S-EPMC11230308 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Publications

Dosimetry of [<sup>64</sup>Cu]FBP8: a fibrin-binding PET probe.

Izquierdo-Garcia David D Désogère Pauline P Philip Anne L AL Sosnovik David E DE Catana Ciprian C Caravan Peter P

medRxiv : the preprint server for health sciences 20240628

<h4>Purpose</h4>This study presents the biodistribution, clearance and dosimetry estimates of [<sup>64</sup>Cu]Fibrin Binding Probe #8 ([<sup>64</sup>Cu]FBP8) in healthy subjects.<h4>Procedures</h4>This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [<sup>64</sup>Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 hours, 4h and 24h ...[more]

PMID: 38978675

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Project description:UnlabelledThe 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.MethodsSprague-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.ConclusionWe 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.

Project description:PurposeCopper is essential for enzymatic processes throughout the body. [64Cu]copper (64Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64Cu in healthy humans by both intravenous and oral administration.MethodsSix healthy participants underwent PET/CT studies with intravenous or oral administration of 64Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs.ResultsAfter intravenous administration, 64Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, 64Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min- 1.Conclusion64Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, while after oral administration, 64Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64Cu yielded images of high quality for both administration forms with radiation doses of approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans.Trial registration numberEudraCT no. 2016-001975-59. Registration date: 19/09/2016.

Project description:BackgroundDespite advances in breast cancer imaging, reliable detection of sentinel lymph node (SLN) metastasis remains challenging. This study aimed to determine the ability of immuno-positron emission tomography (PET) using 64Cu-labeled cetuximab to detect SLN metastasis in a model of epidermal growth factor receptor (EGFR)-positive breast cancer.MethodsThe SLN metastasis model was established using the EGFR-strongly-expressing MDA-MB-468 breast cancer cell line. In this xenograft model, [64Cu]Cu-PCTA-cetuximab was administered intravenously (5.8 ± 0.9 MBq; n = 12) or both intradermally and subdermally into the parapapillary region of the tumor-containing mammary gland (4.3 ± 0.4 MBq; n = 11), after which PET was performed. 18F-FDG PET was also performed intravenously (9.1 ± 1.4 MBq; n = 4) or intradermally/subdermally (5.4 ± 2.2 MBq; n = 3) in the same cohort before [64Cu]Cu-PCTA-cetuximab PET. PET/computed tomography was performed 60 min after administration of 18F-FDG and 24 h after administration of [64Cu]Cu-PCTA-cetuximab. Delayed PET/CT scans were conducted 48 h after administration for all mice in the intradermally/subdermally administered [64Cu]Cu-PCTA-cetuximab group and for four of the 12 mice in the intravenously administered [64Cu]Cu-PCTA-cetuximab group. SLNs were identified using blue dye, and PET and pathological evaluations of the resected SLN were performed to confirm metastases.ResultsAfter intravenous administration of [64Cu]Cu-PCTA-cetuximab (n = 12), accumulation was detected in the primary tumor in all mice and in the axilla of eight mice (67%, SUVmax 1.24 ± 0.51), all of which were found to have SLNs with histologically confirmed metastasis. The sensitivity, specificity, accuracy, and negative and positive predictive values for PET with intravenously administered [64Cu]Cu-PCTA-cetuximab were 89%, 100%, 92%, 75%, and 100%, respectively. In contrast, all mice with intradermal/subdermal administration (n = 11) showed high accumulation in both the primary tumor and axillary lymph nodes (SUVmax 4.28 ± 1.19), with six mice (55%, SUVmax 5.01 ± 1.12) having histologically confirmed metastasis. The sensitivity, specificity, accuracy, and positive predictive values for PET with intradermally/subdermally administered [64Cu]Cu-PCTA-cetuximab were 100%, 0%, 55% and 55%, respectively. SLN metastasis was not detectable by intravenous or intradermal/subdermal 18F-FDG PET.ConclusionsPET with intravenously administered [64Cu]Cu-PCTA-cetuximab demonstrated high precision for diagnosis of SLN metastasis in a xenograft model of EGFR-positive human breast cancer. Although further evaluation is necessary, intradermal/subdermal administration could be a useful therapeutic approach owing to its high accumulation in SLNs.

Project description:Radiometal-labeled peptide-based radiopharmaceuticals (RLPB-radiopharmaceuticals) are promising for cancer imaging and targeted radiotherapy; however, their effectiveness is often compromised by the high retention of nonspecific radioactivity in the kidneys due to renal excretion pathways. Current strategies to address this issue have limitations, highlighting the need for innovative approaches to improve targeting specificity and therapeutic efficacy. We aimed to evaluate the applicability of the Gly-Phe-Lys (GFK) tripeptide, a renal brush border (RBB) enzyme-cleavable linkage, to reduce renal radioactivity in RLPB-radiopharmaceuticals using the integrin-targeting radiopeptide [64Cu]Cu-cyclam-RAFT-c(-RGDfK-)4 ([64Cu]Cu-cyclam-RaftRGD). We designed and synthesized the model compound [64Cu]Cu-cyclam-GFK(benzoyl [Bz]), its predictive metabolites, and GFK-incorporated [64Cu]Cu-cyclam-RaftRGD derivatives [64Cu]Cu-cyclam-GFK-RaftRGD and [64Cu]Cu-cyclam-GFK(beta-alanine [βA])3-RaftRGD. In vitro studies showed that dual radiometabolites, namely, [64Cu]Cu-cyclam-G and [64Cu]Cu-cyclam-GF, were simultaneously released from [64Cu]Cu-cyclam-GFK(Bz) by different RBB enzymes, whereas both RaftRGD derivatives released only [64Cu]Cu-cyclam-GF. When injected into mice, [64Cu]Cu-cyclam-GFK(Bz) and the two RaftRGD derivatives led to the urinary excretion of [64Cu]Cu-cyclam-G and [64Cu]Cu-cyclam-GF, respectively. PET imaging and biodistribution studies showed the increased rates of reduction in renal radioactivity levels for the two RaftRGD derivatives compared to the parental [64Cu]Cu-cyclam-RaftRGD (e.g., PET: 1 to 24 h postinjection, 73.0 ± 2.3 and 75.6 ± 1.8 vs 43.0 ± 4.5%, p < 0.0001; biodistribution: 3 to 24 h, 61.1 and 74.4 vs 22.8%). Taken together, these results indicate that the designed renal cleavage occurred in vivo. We also noted the steric interference of the RaftRGD moiety on enzyme access, the spacer effect of the trimeric βA sequence (reduced steric hindrance), and the altered radiopharmacokinetics (e.g., initially increased renal accumulation) of the RaftRGD compounds upon linker incorporation. These findings provide important insights into the chemical design of RLPB-radiopharmaceuticals with reduced renal retention based on the RBB strategy.

Dataset Information

Dosimetry of [⁶⁴Cu]FBP8: a fibrin-binding PET probe.

Purpose

Procedures

Results

Conclusions

Publications

Dosimetry of [<sup>64</sup>Cu]FBP8: a fibrin-binding PET probe.

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Dataset Information

Dosimetry of [64Cu]FBP8: a fibrin-binding PET probe.

Purpose

Procedures

Results

Conclusions

Publications

Dosimetry of [<sup>64</sup>Cu]FBP8: a fibrin-binding PET probe.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dosimetry of [⁶⁴Cu]FBP8: a fibrin-binding PET probe.