44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617-preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617

Background: The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging (Ga-68) and radionuclide therapy (Lu-177) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced Sc-44 (T-1/2 = 4.04 h) and investigated preclinically for its use as a diagnostic match to Lu-177-PSMA-617. Results: Sc-44 was produced at the research cyclotron at PSI by irradiation of enriched Ca-44 targets, followed by chromatographic separation. Sc-44-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol. Sc-44-PSMA-617 was evaluated in vitro and compared to the Lu-177-and Ga-68-labeled match, as well as Ga-68-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of Lu-177-and Ga-68-labeled PSMA-617. Moreover, Sc-44-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice. Sc-44-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of Sc-44-PSMA-617 resembled that of Lu-177-PSMA-617 most closely, while the Ga-68-labeled ligands, in particular Ga-68-PSMA-11, showed different distribution kinetics. Sc-44-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed. Conclusions: The in vitro characteristics and in vivo kinetics of Sc-44-PSMA-617 were more similar to Lu-177-PSMA-617 than to Ga-68-PSMA-617 and Ga-68-PSMA-11. Due to the almost four-fold longer half-life of Sc-44 as compared to Ga-68, a centralized production of Sc-44-PSMA-617 and transport to satellite PET centers would be feasible. These features make Sc-44-PSMA-617 particularly appealing for clinical application.