61Cu-PSMA-Targeted PET for Prostate Cancer: From Radiotracer Development to First-in-Human Imaging
In this study by Bernabeau et al., the β-CUBE was used for dynamic and static PET scans and to perform biodistribution studies. The β-CUBE scanner aided in providing high-resolution imaging that enabled the detailed preclinical evaluation of tracer distribution and tumor uptake.
Research question
The demand for PET tracers that target prostate-specific membrane antigen (PSMA) continues to increase. Meeting this demand with approved 68Ga- and 18F-labeled PSMA tracers is challenging outside of major urban centers due to the short physical half-life of these radionuclides makes it necessary to produce them near their sites of usage. To overcome this challenge, cyclotron-produced 61Cu for labeling PSMA PET tracers has been proposed as an alternative. 61Cu can be produced on a large scale, and its 3.33-h half-life allows shipping over considerably longer distances than possible for 68Ga and 18F. Production of true theranostic twins using 61Cu and the β−-emitter 67Cu is also feasible. This study reports the development of the first 61Cu-labeled PSMA-targeted tracers.
Experiment
The β-CUBE was used for dynamic and static PET scans and to perform biodistribution studies. Dynamic PET scans (0–1 h) after injection were acquired using the β-CUBE after intravenous administration of 61Cu-labeled tracers (100 µL/400 pmol/7–8 MBq), 68Ga-labeled tracers (100 µL/400 pmol/6–9 MBq), and [18F]PSMA-1007 (100 µL/70 pmol/15 MBq). In addition, static scans at 4 h after injection were acquired for the 61Cu-labeled tracers and [18F]PSMA-1007. Mice were anesthetized with 1.5% isoflurane, and dynamic PET scans were acquired for 30 min. within 1 h after injection.
Results
In vivo [61Cu]Cu-NODAGA-PSMA-I&T showed significantly lower uptake in nontargeted tissues than [61Cu]Cu-DOTAGA-PSMA-I&T and higher tumor uptake than [61Cu]Cu-DOTAGA-PSMA-I&T (, [68Ga]Ga-PSMA-11 , and [18F]PSMA-1007 at 1 h after injection. Tumor uptake was also higher for [61Cu]Cu-NODAGA-PSMA-I&T at 4 h after injection than for [61Cu]Cu-DOTAGA-PSMA-I&T and [18F]PSMA-1007 . Tumor-to-nontumor ratios of [61Cu]Cu-NODAGA-PSMA-I&T were superior to those of [61Cu]Cu-DOTAGA-PSMA-I&T and comparable to those of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 at 1 h after injection and increased significantly between 1 and 4 h after injection in most cases.
The first figure shows the dynamic PET/CT scans of [61Cu] Cu-DOTAGA-PSMA-I&T and [61Cu]Cu-NODAGA-PSMA-I&T, respectively, from 0 to 1 h after injection. Time–activity curves showed uptake in the tumor within minutes after injection, an uptake peak of approximately 30 minutes, and stability remaining for up to 60 minutes.
The second figure compares PET/CT imaging of an early versus a late time point (1 vs. 4h after injection). [61Cu]Cu-DOTAGA-PSMA-I&T accumulated mainly in the liver, kidneys, intestine, and gallbladder. Undesirable accumulation in the abdomen, especially the liver and intestines, was predominant at 4 h after injection. In contrast, [61Cu]Cu-NODAGA-PSMA-I&T showed a favorable biodistribution profile with renal accumulation and persistent tumor uptake between 1 and 4 h after injection.
[61Cu]Cu-NODAGA-PSMA-I&T showed clear advantages over [61Cu]Cu-DOTAGA-PSMA-I&T, including higher tumor uptake and lower abdominal activity, as confirmed by dynamic and static imaging. First-in-human imaging validated these findings, showing clear visualization of multifocal osseous and hepatic metastases, reinforcing the clinical promise of [61Cu]Cu-NODAGA-PSMA-I&T for prostate cancer diagnostics. Overall, the findings of this study serve as a foundation for future clinical development of 61Cu-labeled tracers and suggest opportunities for development of other 61Cu-labeled tracers for a range of clinically valuable targets.
