First-in-human study of a novel bifunctional PET tracer [68Ga]Ga-DOTA-NI-FAPI-04 targeting FAP and hypoxia.

PURPOSE: Preclinical studies have demonstrated that [68Ga]Ga/[177Lu]Lu-DOTA-NI-FAPI-04, a bivalent agent containing an extra hypoxia-sensitive 2-nitroimidazole (NI) group, exhibited favorable tumor binding affinity and improved tumor uptake and retention than [68Ga]Ga/[177Lu]Lu-DOTA-FAPI-04. This study aims to further investigate the value of clinical application for [68Ga]Ga-DOTA-NI-FAPI-04 PET/CT via a direct head-to-head comparison with [68Ga]Ga-DOTA-FAPI-04.

METHODS

A total of 50 patients underwent paired [68Ga]Ga-DOTA-NI-FAPI-04 and [68Ga]Ga-DOTA-FAPI-04 PET/CT within 1 week interval. Among these, four patients underwent serial dynamic [68Ga]Ga-DOTA-NI-FAPI-04 PET scans for dosimetry evaluation, and the others underwent scans at 60 min and 120 min. Additionally, we calculated the SUVmax differences (ΔSUVmax) by [68Ga]Ga-DOTA-NI-FAPI-04 minus [68Ga]Ga-DOTA-FAPI-04 PET/CT for further analysis. Immunohistochemistry for FAP and hypoxia-inducible factor-1 alpha (HIF-1α) was performed in 22 primary tumors.

RESULTS

The effective absorbed dose of [68Ga]Ga-DOTA-NI-FAPI-04 PET/CT was calculated as 1.95E-02 mSv/MBq. Tumor uptake of [68Ga]Ga-DOTA-NI-FAPI-04 showed rapid uptake and steady values (average SUVmax 11.6-13.0 from 3 to 120 min). [68Ga]Ga-DOTA-NI-FAPI-04 exhibited significantly higher uptake in tumor lesions compared to [68Ga]Ga-DOTA-FAPI-04 PET/CT, particularly in primary tumors (P < 0.05), nodal metastases (P < 0.001), bone metastases (P < 0.001), and liver metastases (P < 0.05). That of FAP expression was correlated with that of HIF-1α (r = 0.661, P < 0.001), and the expression of HIF-1α showed a positive correlation with ΔSUVmax (r = 0.528, P = 0.011).

CONCLUSION

[68Ga]Ga-DOTA-NI-FAPI-04 showed significantly higher tumor uptake and retention over [68Ga]Ga-DOTA-FAPI-04, with particularly enhanced visualization of hypoxic lesions, suggesting that hypoxia-sensitive moiety may play an important role in detection of tumors. Further study of [177Lu]Lu-DOTA-NI-FAPI-04 in humans is warranted to explore its clinical applications. URL OF REGISTRY: https://clinicaltrials.gov/study/NCT06688305 .

TRIAL REGISTRATION: ClinicalTrials.gov, NCT06688305, Registered 14 November 2024, retrospectively registered.