Preclinical Evaluation in Animals for the Efficacy, Dosimetry, and Safety of [ ⁶⁸ Ga]Ga/[ ¹⁷⁷ Lu]Lu-TVS-PSMA Radioligands, and First-in-Human Study of [ ⁶⁸ Ga]Ga-TVS-PSMA-1

To improve the theranostic efficacy of PSMA-targeted radiopharmaceuticals on patients with medium-to-low PSMA expression, we radiolabeled a series of novel designed PSMA-targeting dimer agents to improve tumor imaging and treatment outcomes under challenging conditions. All agents were successfully radiolabeled with 68 Ga in moderate decay-corrected labeling yield and high radiochemical purity. Among them, [ 68 Ga]Ga-TVS-PSMA- 1 exhibited high tumor uptake in both LNCaP and 22RV1 models. [ 177 Lu]Lu-TVS-PSMA- 1 demonstrated significantly improved treatment efficacy with a lower dose and good safety profile compared with [ 177 Lu]Lu-PSMA-617. A first-in-human [ 68 Ga]Ga-TVS-PSMA- 1 PET/CT scan was performed in a 66-year-old male prostate cancer patient. Two metastatic lesions in the lumbar vertebrae were clearly visualized, and the primary tumor exhibited an SUVmax of 30.3. The [ 68 Ga]Ga-TVS-PSMA- 1 showed lower salivary gland uptake compared with previously reported values for [ 68 Ga]Ga-PSMA-11; however, confirmation in larger patient cohorts is required. This study demonstrates that the dimer agent TVS-PSMA- 1 holds great potential as a next-generation theranostic agent for prostate cancer.