PSMA-GCK01: A Generator-Based (99m)Tc/(188)Re Theranostic Ligand for the Prostate-Specific Membrane Antigen

Prostate-specific membrane antigen (PSMA) theranostics have been introduced with (68)Ga and (177)Lu, the most used radionuclides. However, (188)Re is a well-known generator-based therapeutic nuclide that completes a theranostic tandem with (99m)Tc and may offer an interesting alternative to the currently used radionuclides. In the present work, we aimed at the development of a PSMA-targeted (99m)Tc/(188)Re theranostic tandem. Methods: The ligand HYNIC-iPSMA was chosen as the lead structure. Its HYNIC chelator has limitations for (188)Re labeling and was replaced by mercaptoacetyltriserine to obtain PSMA-GCK01, a precursor for stable (99m)Tc and (188)Re labeling. (99m)Tc-PSMA-GCK01 was used for in vitro evaluation of the ligand and comparison with (99m)Tc-EDDA/HYNIC-iPSMA. Planar imaging using (99m)Tc-PSMA-GCK01 and organ biodistribution with (188)Re-PSMA-GCK01 were performed using LNCaP tumor–bearing mice. Finally, the theranostic tandem was applied for imaging and therapy in 3 prostate cancer patients in compassionate care. Results: Efficient radiolabeling of PSMA-GCK01 with both radionuclides was demonstrated. Cell-based assays with (99m)Tc-PSMA-GCK01 versus (99m)Tc-EDDA/HYNIC-iPSMA revealed comparable uptake characteristics. Planar imaging and organ distribution revealed good tumor uptake of both (99m)Tc-PSMA-GCK01 and (188)Re-PSMA-GCK01 at 1 and 3 h after injection, with low uptake in nontarget organs. In patients, similar distribution patterns were observed for (99m)Tc-PSMA-GCK01 and (188)Re-PSMA-GCK01 and in comparison with (177)Lu-PSMA-617. Conclusion: The ligand PSMA-GCK01 labels stably with (99m)Tc and (188)Re, both generator-based radionuclides, and thus provides access to on-demand labeling at reasonable costs. Preclinical evaluation of the compounds revealed favorable characteristics of the PSMA-targeted theranostic tandem. This result was confirmed by successful translation into first-in-humans application.