PSMA-GCK01: A Generator-Based 99mTc/188Re Theranostic Ligand for the Prostate-Specific Membrane Antigen

• Published in: The Journal of nuclear medicine (1978) Vol. 64; no. 7; pp. 1069 - 1075
• Main Authors: Cardinale, Jens, Giesel, Frederik L, Wensky, Christina, Rathke, Hendrik G, Haberkorn, Uwe, Kratochwil, Clemens
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.07.2023
• Subjects: Antigens; Basic Science Investigation; Labeling; Labels; Ligands; Lutetium isotopes; Medical imaging; Membranes; Precision medicine; Prostate; Prostate cancer; Radioisotopes; Radiolabelling; Tumors
• ISSN: 0161-5505; 1535-5667; 1535-5667
• DOI: 10.2967/jnumed.122.264944

Prostate-specific membrane antigen (PSMA) theranostics have been introduced with 68Ga and 177Lu, the most used radionuclides. However, 188Re is a well-known generator-based therapeutic nuclide that completes a theranostic tandem with 99mTc and may offer an interesting alternative to the currently used radionuclides. In the present work, we aimed at the development of a PSMA-targeted 99mTc/188Re theranostic tandem. Methods: The ligand HYNIC-iPSMA was chosen as the lead structure. Its HYNIC chelator has limitations for 188Re labeling and was replaced by mercaptoacetyltriserine to obtain PSMA-GCK01, a precursor for stable 99mTc and 188Re labeling. 99mTc-PSMA-GCK01 was used for in vitro evaluation of the ligand and comparison with 99mTc-EDDA/HYNIC-iPSMA. Planar imaging using 99mTc-PSMA-GCK01 and organ biodistribution with 188Re-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 99mTc-PSMA-GCK01 versus 99mTc-EDDA/HYNIC-iPSMA revealed comparable uptake characteristics. Planar imaging and organ distribution revealed good tumor uptake of both 99mTc-PSMA-GCK01 and 188Re-PSMA-GCK01 at 1 and 3 h after injection, with low uptake in nontarget organs. In patients, similar distribution patterns were observed for 99mTc-PSMA-GCK01 and 188Re-PSMA-GCK01 and in comparison with 177Lu-PSMA-617. Conclusion: The ligand PSMA-GCK01 labels stably with 99mTc and 188Re, 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.