@article {Cardinalejnumed.122.264944, author = {Jens Cardinale and Frederik L. Giesel and Christina Wensky and Hendrik G. Rathke and Uwe Haberkorn and Clemens Kratochwil}, title = {PSMA-GCK01 - A Generator-Based 99mTc-/188Re-Theranostic Ligand for the Prostate-Specific Membrane Antigen}, elocation-id = {jnumed.122.264944}, year = {2023}, doi = {10.2967/jnumed.122.264944}, publisher = {Society of Nuclear Medicine}, abstract = {Introduction: Prostate-specific membrane antigen (PSMA)-theranostic has been introduced with Gallium-68 and Lutetium-177, the currently most used radionuclides. However, Rhenium-188 is a well-known generator based therapeutic nuclide completing a theranostic tandem with Technetium-99m and may offer an interesting alternative to the current state of the art. In the present work, we aimed towards the development of a PSMA-targeted 99mTc-/188Re-theranostic tandem. Methods: The ligand HYNIC-iPSMA was chosen as lead structure. Its HYNIC chelator has limitations for 188Re-labeling and was exchanged by MAS3 to obtain PSMA-GCK01, as precursor for stable 99mTc- and 188Re-labeling. [99mTc]Tc-PSMA-GCK01 was used for the in-vitro evaluation of the novel ligand and comparison with [99mTc]Tc-EDDA/HYNIC-iPSMA. Planar imaging using 99mTc-PSMA-GCK01 and organ biodistribution with 188Re-PSMA-GCK01 were done using LNCaP-tumor bearing mice, respectively. Finally, the theranostic tandem was applied for imaging and therapy in three prostate cancer patients in compassionate care. Results: An efficient radiolabeling of PSMA-GCK01 with both radionuclides was demonstrated. Cell-based assays with 99mTc-PSMA-GCK01 vs 99mTc-EDDA/HYNIC-iPSMA revealed comparable uptake characteristics. Planar imaging and organ distribution revealed a good tumor uptake of both, 99mTc- and 188Re-PSMA-GCK01 at 1 h and 3 h p.i. with low uptake in non-target organs. In patients, similar distribution patterns were observed for 99mTc-PSMA-GCK01 and 188Re-PSMA-GCK01 and also in comparison of Tc/Re-PSMA-GCK01 with 177Lu-PSMA-617. Conclusion: The novel ligand PSMA-GCK01 labels stable with 99mTc- and 188Re - both are generator based radionuclides {\textendash} and, thus, provides access to on-demand labeling at reasonable costs. The preclinical evaluation of the compounds revealed favorable characteristics of the PSMA-targeted theranostic tandem. This result was further confirmed by a successful translation into first-in-human application.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/early/2023/02/09/jnumed.122.264944}, eprint = {https://jnm.snmjournals.org/content/early/2023/02/09/jnumed.122.264944.full.pdf}, journal = {Journal of Nuclear Medicine} }