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 <a href="https://clinicaltrials.gov/study/NCT06688305">https://clinicaltrials.gov/study/NCT06688305</a>. Trial registration ClinicalTrials.gov, NCT06688305, Registered 14 November 2024, retrospectively registered.

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

期刊论文
发表日期：

2025年10月31日

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Jie Zang,
Hongfei Cheng,
Yang Luo,
Wenbin Jin,
Yuxin Lai,
Qingming Zheng,
Yumeng Peng,
Hank F. Kung,
Lin Zhu,
Chunlin Ke,
Chen liu,
Weibing Miao

摘要

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 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.

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 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).

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.

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

摘要

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