PSMA-GCK01: A Generator-Based<sup>99m</sup>Tc/<sup>188</sup>Re Theranostic Ligand for the Prostate-Specific Membrane Antigen
Jens Cardinale, Frederik L. Giesel, Christina Wensky, Hendrik G. Rathke, Uwe Haberkorn, Clemens Kratochwil
Abstract
<b>Introduction:</b> 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 <sup>99m</sup>Tc-/<sup>188</sup>Re-theranostic tandem. <b>Methods:</b> The ligand HYNIC-iPSMA was chosen as lead structure. Its HYNIC chelator has limitations for <sup>188</sup>Re-labeling and was exchanged by MAS3 to obtain PSMA-GCK01, as precursor for stable <sup>99m</sup>Tc- and <sup>188</sup>Re-labeling. [<sup>99m</sup>Tc]Tc-PSMA-GCK01 was used for the in-vitro evaluation of the novel ligand and comparison with [<sup>99m</sup>Tc]Tc-EDDA/HYNIC-iPSMA. Planar imaging using <sup>99m</sup>Tc-PSMA-GCK01 and organ biodistribution with <sup>188</sup>Re-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. <b>Results:</b> An efficient radiolabeling of PSMA-GCK01 with both radionuclides was demonstrated. Cell-based assays with <sup>99m</sup>Tc-PSMA-GCK01 vs <sup>99m</sup>Tc-EDDA/HYNIC-iPSMA revealed comparable uptake characteristics. Planar imaging and organ distribution revealed a good tumor uptake of both, <sup>99m</sup>Tc- and <sup>188</sup>Re-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 <sup>99m</sup>Tc-PSMA-GCK01 and <sup>188</sup>Re-PSMA-GCK01 and also in comparison of Tc/Re-PSMA-GCK01 with <sup>177</sup>Lu-PSMA-617. <b>Conclusion:</b> The novel ligand PSMA-GCK01 labels stable with <sup>99m</sup>Tc- and <sup>188</sup>Re - both are generator based radionuclides – 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.