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

Abstract

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. 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 SUV_max differences (ΔSUV_max) 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. 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 SUV_max 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 ΔSUV_max (r = 0.528, P = 0.011). [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 . ClinicalTrials.gov, NCT06688305, Registered 14 November 2024, retrospectively registered.