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 (⁶⁸Ga) and radionuclide therapy (¹⁷⁷Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced ⁴⁴Sc (T_1/2 = 4.04 h) and investigated preclinically for its use as a diagnostic match to ¹⁷⁷Lu-PSMA-617.
Results: ⁴⁴Sc was produced at the research cyclotron at PSI by irradiation of enriched ⁴⁴Ca targets, followed by chromatographic separation. ⁴⁴Sc-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. ⁴⁴Sc-PSMA-617 was evaluated in vitro and compared to the ¹⁷⁷Lu- and ⁶⁸Ga-labeled match, as well as ⁶⁸Ga-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 ¹⁷⁷Lu- and ⁶⁸Ga-labeled PSMA-617. Moreover, ⁴⁴Sc-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. ⁴⁴Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of ⁴⁴Sc-PSMA-617 resembled that of ¹⁷⁷Lu-PSMA-617 most closely, while the ⁶⁸Ga-labeled ligands, in particular ⁶⁸Ga-PSMA-11, showed different distribution kinetics. ⁴⁴Sc-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 ⁴4Sc-PSMA-617 were more similar to ¹⁷⁷Lu-PSMA-617 than to ⁶⁸Ga-PSMA-617 and ⁶⁸Ga-PSMA-11. Due to the almost four-fold longer half-life of ⁴⁴Sc as compared to ⁶⁸Ga, a centralized production of ⁴⁴Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make ⁴⁴Sc-PSMA-617 particularly appealing for clinical application.