Liquid Chromatography ICP-MS to Assess the Stability of ¹⁷⁵Lu- and ^natGa-Based Tumor-Targeting Agents towards the Development of ¹⁷⁷Lu- and ⁶⁸Ga-Labeled Radiopharmaceuticals

In recent years, nuclear medicine has gained great interest, partly due to the success story of [Lu-177]Lu-PSMA-617 (Pluvicto (TM)). Still, in-depth preclinical characterization of radiopharmaceuticals mainly happens at centers that allow working with radioactive material. To support the development of novel radiopharmaceuticals, alternative non-radioactive characterization assays are highly desirable. The aim of this study was to demonstrate that inductively coupled plasma mass spectrometry (ICP-MS) associated with a chromatographic system can serve as a surrogate for the classical high-performance liquid chromatography (HPLC)-radiodetector combination for preclinical in vitro characterization of non-radioactive metal-labeled analogs of radiopharmaceuticals. In this proof-of-concept study, we demonstrate the applicability of HPLC-ICP-MS by assessing the stability of Lu-175- and Ga-nat-labeled prostate-specific membrane antigen (PSMA)-targeting peptidomimetics, single domain antibody (sdAb) conjugates, and monoclonal antibody (mAb) conjugates. Lu-175-labeled DOTAGA-conjugated and Ga-nat-labeled NODAGA-conjugated sdAbs and mAbs showed the highest stability with >90% still intact after 24 h. The peptidomime-tics [Lu-175]Lu-PSMA-617 and [Ga-nat]Ga-PSMA-11 showed identical in vitro serum stability as it was reported for their corresponding radioligands with >99% intact species after 24 h incubation in mouse serum, demonstrating the reliability of the method. Hence, the established HPLC-ICP-MS methods can support the development of novel radiopharmaceuticals in a classical pharmaceutical setting.