Preclinical Evaluation in Animals for the Efficacy, Dosimetry, and Safety of [68Ga]Ga/[177Lu]Lu-TVS-PSMA Radioligands, and First-in-Human Study of [68Ga]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 68Ga in moderate decay-corrected labeling yield and high radiochemical purity. Among them, [68Ga]Ga-TVS-PSMA-1 exhibited high tumor uptake in both LNCaP and 22RV1 models. [177Lu]Lu-TVS-PSMA-1 demonstrated significantly improved treatment efficacy with a lower dose and good safety profile compared with [177Lu]Lu-PSMA-617. A first-in-human [68Ga]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 [68Ga]Ga-TVS-PSMA-1 showed lower salivary gland uptake compared with previously reported values for [68Ga]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.