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

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Abstract
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.
Funding Information
  • Sichuan Provincial Science and Technology Support Program (2025ZDZX0046)
  • Gansu Isotope Laboratory (GSTWS2501)
  • Luzhou Science and Technology Program (2025LZXNYDJC04)

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