Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

Persson, Morten; Ali, Henrik H. El; Binderup, Tina; Pfeifer, Andreas; Madsen, Jacob; Rasmussen, Palle; Kjær, Andreas

doi:10.1016/j.nucmedbio.2013.12.007

Cited by 24 publications

(25 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we demonstrated in our phase 1 study sufficient in vivo stability of the 64 Cu-DOTA complex to obtain good-quality images (14), which we have also confirmed in preclinical studies comparing DOTA with other chelates (17)(18)(19). Data from our first-in-human study of 14 patients demonstrated that imaging was feasible using an activity of 200 MBq, with a favorable dosimetry of only 6.3 mSv (14).…”

supporting

confidence: 74%

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients

et al. 2015

Self Cite

View full text Add to dashboard Cite

Neuroendocrine tumors (NETs) can be visualized using radiolabeled somatostatin analogs. We have previously shown the clinical potential of 64 Cu-DOTATATE in a small first-in-human feasibility study. The aim of the present study was, in a larger prospective design, to compare on a head-to-head basis the performance of 64 In-diethylenetriaminepentaacetic acid (DTPA)-octreotide ( 111 In-DTPA-OC) as a basis for implementing 64 Cu-DOTATATE as a routine. Methods: We prospectively enrolled 112 patients with pathologically confirmed NETs of gastroenteropancreatic or pulmonary origin. All patients underwent both PET/CT with 64 Cu-DOTATATE and SPECT/CT with 111 In-DTPA-OC within 60 d. PET scans were acquired 1 h after injection of 202 MBq (range, 183-232 MBq) of 64 Cu-DOTATATE after a diagnostic contrast-enhanced CT scan. Patients were followed for 42-60 mo for evaluation of discrepant imaging findings. The McNemar test was used to compare the diagnostic performance. Results: Eightyseven patients were congruently PET-and SPECT-positive. No SPECT-positive cases were PET-negative, whereas 10 false-negative SPECT cases were identified using PET. The diagnostic sensitivity and accuracy of 64 Cu-DOTATATE (97% for both) were significantly better than those of 111 In-DTPA-OC (87% and 88%, respectively, P 5 0.017). In 84 patients (75%), 64 Cu-DOTATATE identified more lesions than 111 In-DTPA-OC and always at least as many. In total, twice as many lesions were detected with 64 Cu-DOTATATE than with 111 In-DTPA-OC. Moreover, in 40 of 112 cases (36%) lesions were detected by 64 Cu-DOTATATE in organs not identified as disease-involved by 111 In-DTPA-OC. Conclusion: With these results, we demonstrate that 64 Cu-DOTATATE is far superior to 111 In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of 64 Cu-DOTATATE as a replacement for 111 In-DTPA-OC.

show abstract

supporting

confidence: 74%

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The difference in clearance profiles may be due to the presence of an extra carboxylate that is present on DA, which could provide increased kinetic stability of the chelation complex in vivo while also increasing hydrophilicity. Notable 64 Cu-MMC(IR800)-TOC accumulation was also found in the intestines at 4 h after injection (12.9 6 2.9 %ID/g) but decreased at 24 h (3.5 6 0.4 %ID/g) and is in agreement with preclinical data with 64 Cu-DOTA-peptides (31,32) and clinical data with 64 Cu-DOTATATE (14). Although signal in nontumor tissues decreased over time (Fig.…”

Section: Discussionsupporting

confidence: 85%

A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting

et al. 2017

View full text Add to dashboard Cite

Fluorescence-guided surgery is an emerging imaging technique that can enhance the ability of surgeons to detect tumors when compared with visual observation. To facilitate characterization, fluorescently labeled probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. In this study, we selected the somatostatin receptor imaging agent DOTATOC as the foundation for developing a dual-labeled analog. We hypothesized that a customized dual-labeling approach with a multimodality chelation (MMC) scaffold would minimize steric effects of dye conjugation and retain agonist properties. An MMC conjugate (MMC-TOC) was synthesized on solid-phase and compared with an analog prepared using conventional methods (DA-TOC). Both analogs were conjugated to IRDye 800 using copper-free click chemistry. The resulting compounds, MMC(IR800)-TOC and DA(IR800)-TOC, were labeled with Cu andCu and tested in vitro in somatostatin receptor subtype 2-overexpressing HEK-293 cells to assess agonist properties, and in AR42J rat pancreatic cancer cells to determine receptor binding characteristics. Multimodality imaging was performed in AR42J xenografts. Cu-MMC(IR800)-TOC demonstrated higher potency for cyclic adenosine monophosphate inhibition (half maximal effective concentration [EC]: 0.21 ± 0.18 vs. 1.38 ± 0.54 nM) and receptor internalization (EC: 41.9 ± 29.8 vs. 455 ± 299 nM) than Cu-DA(IR800)-TOC. Radioactive uptake studies showed that blocking with octreotide caused a dose-dependent reduction in Cu-MMC(IR800)-TOC uptake whereasCu-DA(IR800)-TOC was not affected. In vivo studies revealed higher tumor uptake for Cu-MMC(IR800)-TOC thanCu-DA(IR800)-TOC (5.2 ± 0.2 vs. 3.6 ± 0.4 percentage injected dose per gram). In vivo blocking studies with octreotide reduced tumor uptake of Cu-MMC(IR800)-TOC by 66%. Excretion ofCu-MMC(IR800)-TOC was primarily through the liver and spleen whereas Cu-DA(IR800)-TOC was cleared through the kidneys. Ex vivo analysis at 24 h confirmed PET/CT data by showing near-infrared fluorescence signal in tumors and a tumor-to-muscle ratio of 5.3 ± 0.8 as determined by γ-counting. The findings demonstrate that drug design affected receptor pharmacology and suggest that the MMC scaffold is a useful tool for the development of dual-labeled imaging agents.

show abstract

“…Importantly, no adverse events or clinically detectable pharmacologic effects were found. Radiation dosimetry analysis estimated an effective dose of 0.0276 mSv/MBq, closely resembling the predicted effective dose from our previous mouse study [43], and equaling 5.5 mSv for a 200 MBq dose, which is lower/comparable radiation dose to the dose received from a standard FDG-PET [44]. Secondary objectives were to investigate the uptake in primary tumor lesions and potential metastases.…”

Section: Upar Pet Imaging In Patients With Pcsupporting

confidence: 66%

PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives

Skovgaard

Persson²,

Kjær

2016

Clin Transl Imaging

Self Cite

View full text Add to dashboard Cite

Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)—provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer 64Cu-DOTA-AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome.

show abstract

Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

Abstract: Favorable dosimetry estimates together with previously reported uPAR PET data fully support human testing of (64)Cu-DOTA-AE105.

Cited by 24 publications

References 32 publications

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients

A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting

PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives

Contact Info

Product

Resources

About

Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

Abstract: Favorable dosimetry estimates together with previously reported uPAR PET data fully support human testing of (64)Cu-DOTA-AE105.

Cited by 24 publications

References 32 publications

64Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111In-DTPA-Octreotide in 112 Patients

64Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111In-DTPA-Octreotide in 112 Patients

A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting

PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives

Contact Info

Product

Resources

About

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients

⁶⁴Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with ¹¹¹In-DTPA-Octreotide in 112 Patients