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

Jie Zang ^1,2, Hongfei Cheng ^1,2, Yang Luo ³

¹Department of Nuclear Medicine, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fujian Province, Fuzhou, 350212, China.
²Department of Nuclear Medicine, the First Affiliated Hospital, Fujian Medical University, Fujian Province, Fuzhou, 350005, China.
³College of Chemistry, Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing, 100875, China.
⁴School of Medical Imaging, Fujian Medical University, Fujian Province, Fuzhou, 350122, China.
⁵Department of Radiology, University of Pennsylvania, PA, Philadelphia, 19104, USA.
⁶Department of Radiotherapy, the First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fujian Province, Fuzhou, 350005, China. 296200383@fjmu.edu.cn.
⁷Department of Oncology, the First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fujian Province, Fuzhou, 350005, China. 175696700@qq.com.
⁸Department of Nuclear Medicine, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fujian Province, Fuzhou, 350212, China. miaoweibing@126.com.
⁹Department of Nuclear Medicine, the First Affiliated Hospital, Fujian Medical University, Fujian Province, Fuzhou, 350005, China. miaoweibing@126.com.
¹⁰Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fujian Province, Fuzhou, 350005, China. miaoweibing@126.com.

⁰Department of Nuclear Medicine, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fujian Province, Fuzhou, 350212, China.

European Journal of Nuclear Medicine and Molecular Imaging +

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October 31, 2025

View abstract on PubMed

Summary

[68Ga]Ga-DOTA-NI-FAPI-04 PET/CT shows superior tumor uptake compared to [68Ga]Ga-DOTA-FAPI-04, especially in hypoxic lesions. This highlights the potential of hypoxia-sensitive agents for improved cancer detection and diagnosis.

Area Of Science

Radiopharmaceuticals
Molecular Imaging
Oncology

Background

Preclinical studies indicated [68Ga]Ga/[177Lu]Lu-DOTA-NI-FAPI-04 has better tumor binding and uptake than [68Ga]Ga/[177Lu]Lu-DOTA-FAPI-04.
The NI group in [68Ga]Ga-DOTA-NI-FAPI-04 is sensitive to hypoxia.

Purpose Of The Study

To evaluate the clinical utility of [68Ga]Ga-DOTA-NI-FAPI-04 PET/CT.
Directly compare [68Ga]Ga-DOTA-NI-FAPI-04 with [68Ga]Ga-DOTA-FAPI-04 in patients.

Main Methods

50 patients underwent paired [68Ga]Ga-DOTA-NI-FAPI-04 and [68Ga]Ga-DOTA-FAPI-04 PET/CT scans.
Dosimetry and serial dynamic scans were performed for [68Ga]Ga-DOTA-NI-FAPI-04.
Immunohistochemistry for FAP and HIF-1α was conducted on 22 primary tumors.

Main Results

[68Ga]Ga-DOTA-NI-FAPI-04 demonstrated significantly higher tumor uptake than [68Ga]Ga-DOTA-FAPI-04 across primary, nodal, bone, and liver metastases.
FAP expression correlated with HIF-1α expression (r=0.661, P<0.001).
HIF-1α expression positively correlated with increased uptake difference (ΔSUVmax) (r=0.528, P=0.011).

Conclusions

[68Ga]Ga-DOTA-NI-FAPI-04 offers superior tumor uptake and retention, enhancing visualization of hypoxic lesions.
Hypoxia-sensitive moieties are crucial for improved tumor detection.
Further investigation of [177Lu]Lu-DOTA-NI-FAPI-04 in humans is recommended.

Keywords:

FAPI Hypoxia Nitroimidazole PET/CT

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