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⁶⁴Cu-DOTHA₂-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

ABSTRACT: Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. This preclinical study aimed to evaluate the biological and imaging properties of 64Cu-DOTHA2-PSMA. Its stability was assessed in plasma ex vivo and in mice. Cellular behavior was studied for up to 48 h in LNCaP cells. Biodistribution studies were performed in balb/c mice for up to 48 h. Dynamic (1 h) and static (4 h and 24 h) PET imaging was completed in LNCaP tumor-bearing mice. 64Cu-DOTHA2-PSMA was stable ex vivo in plasma and reached cellular internalization up to 34.1 ± 4.9% injected activity (IA)/106 cells at 48 h post-injection (p.i.). Biodistribution results showed significantly lower uptake in kidneys than 68Ga-PSMA-617, our reference PET tracer (p < 0.001), but higher liver uptake at 2 h p.i. (p < 0.001). PET images showed 64Cu-DOTHA2-PSMA’s highest tumoral uptake at 4 h p.i., with a significant difference between blocked and non-blocked groups from the time of injection to 24 h p.i. The high stability and tumor uptake with a long tumor imaging time window of 64Cu-DOTHA2-PSMA potentially contribute to the prostate cancer theranostic approach and its local recurrence detection.

SUBMITTER: Milot MC

PROVIDER: S-EPMC9412875 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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<sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

Milot Marie-Christine MC Benesty Ophélie Bélissant OB Dumulon-Perreault Véronique V Ait-Mohand Samia S Richard Patrick O PO Rousseau Étienne É Guérin Brigitte B

Pharmaceuticals (Basel, Switzerland) 20220813 8

Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. This preclinical study aimed to evaluate the biological and imaging properties of 64Cu-DOTHA2-PSMA. Its stability was assessed in plasma ex vivo and in mice. Cellular behavior was studied for up to 48 ...[more]

PMID: 36015144

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Project description:BackgroundDiacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (64Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression.MethodsμPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. Thereafter, the brains were withdrawn for further autoradiography and immunohistochemistry. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels.ResultsIn vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. In vitro results show that 64Cu-ATSM showed an increase in the uptake only in severe hypoxia at 0.5 and 0.2% of oxygen while for 64Cu-Cl2, the cell retention was significantly increased at 5% and 1% of oxygen with no significant rise at lower oxygen percentages.ConclusionIn the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metabolism and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.

Project description:PurposeProstate-specific membrane antigen positron emission tomography (PSMA-PET) guided targeted biopsy has shown potential for detecting more prostate cancer (PCa) cases. However, relying exclusively on imaging may risk missing lesions, an issue that could be addressed by incorporating radiation-guided technology. Accordingly, we aimed to develop a novel PSMA radiotracer with a long half-life, [64Cu]Cu-DOTA-PSMA-3Q, and evaluate its targeting accuracy. Additionally, this research explored the practicability of real-time lesion verification during surgical interventions.MethodsIn this study, we synthesized the radiotracer [64Cu]Cu-DOTA-PSMA-3Q and verified its PSMA specificity and safety. We prospectively enrolled 18 patients with suspected PCa for PET/CT imaging to assess the efficacy of PCa detection; 10 patients underwent targeted biopsy combined with standard template biopsy at an interval of 24 h after injection. The radioactivity of the biopsy tissue was quantified in counts per minute (CPM) using a gamma spectrometer intraoperatively.ResultsThe efficacy and specificity of [64Cu]Cu-DOTA-PSMA-3Q were confirmed through preclinical cell and animal studies. In clinical settings, PET/CT imaging performed 2 h after injection visualized all of the PSMA-positive lesions both within and outside the prostate. The assessment of human organ radiation exposure indicated that the kidneys received the highest absorbed dose, followed by the bladder wall, salivary glands, and liver. In 10 patients, a total of 132 biopsy cores were extracted, with 53 cores histologically confirmed as PCa. The median CPM for PCa tissues was significantly greater at 134,148 CPM compared to 18,39 CPM for normal prostate tissues (P < 0.001). Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.8837, suggesting high diagnostic accuracy. The optimal diagnostic cut-off was established at 66 CPM, achieving a sensitivity of 77.36%.ConclusionsRadiation-guided technology using [64Cu]Cu-DOTA-PSMA-3Q improves the reliability of PSMA-PET image-guided biopsy, enables instant confirmation of sample lesions during surgical procedures, and holds potential for achieving optimized puncture outcomes.Trial registrationChinese Clinical Trial Registry ChiCTR2300072655, Registered 20 June 2023.

Dataset Information

⁶⁴Cu-DOTHA₂-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

Publications

<sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

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Dataset Information

64Cu-DOTHA2-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

Publications

<sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

⁶⁴Cu-DOTHA₂-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window.