Trop2 immuno-PET/CT imaging of prostate cancer: a proof-of-concept translational study.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of death in men and is highly prone to metastasis. This study aims to develop the novel immuno-PET/CT tracer targeting trophoblast cell surface antigen 2 (Trop2), a transmembrane protein overexpressed in aggressive prostate malignancies, and to investigate its diagnostic value in preclinical studies as well as its potential utility in detecting metastases in PCa patients. METHODS: Integrated analysis of TCGA, GEO, and HPA datasets revealed Trop2 overexpression in prostate adenocarcinoma. By labeling two Trop2-targeted nanobodies (His-tagged T4 and His-tag-free RT4) with (68)Ga and (18)F, we synthesized three radiotracers, [(68)Ga]Ga-NOTA-T4, [(18)F]AlF-RESCA-T4, and [(18)F]AlF-RESCA-RT4. Preclinical validation included cellular assays and xenograft studies for (68)Ga/(18)F-T4 variants, followed by a first-in-human trial evaluating [(18)F]AlF-RESCA-RT4 in ten treatment-naïve PCa patients. RESULTS: Bioinformatics analysis demonstrated Trop2 as a promising target for PCa diagnosis and treatment. In preclinical studies, both [(68)Ga]Ga-NOTA-T4 and [(18)F]AlF-RESCA-T4 illustrated high affinity to Trop2, specific tumor uptake (4.33 ± 0.38 %ID/g and 5.50 ± 0.69 %ID/g at 60 min, respectively) in Trop2-positive xenograft mouse models with minimal background distribution. In the translational study, [(18)F]AlF-RESCA-RT4 outperformed standard [(18)F]-FDG imaging in metastatic prostate cancer patients, detecting 62.4% more lymph node metastases (SUVmax 21.58 ± 13.12 vs. 4.80 ± 1.77) and 69.4% more bone lesions (SUVmax 7.83 ± 4.32 vs. 4.72 ± 1.22). No adverse events were observed. CONCLUSIONS: This work successfully establishes that Trop2 is a new biomarker for PCa, and Trop2 immuno-PET/CT imaging can detect PCa lymph node and osseous metastases. The superior tumor-to-background contrast and clinical safety of [(18)F]AlF-RESCA-RT4 support its translational potential to guide Trop2-targeted therapies and enhance personalized treatment strategies. TRIAL REGISTRATION: NCT06851663. Retrospectively registered 02/24/2025.