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Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In this study, a novel aluminium-[18F]fluoride (Al18F)-labelled 1,4,7‑triazacyclononane-N,N′,N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named Al18F-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of Al18F-NOTA-FAPI was further validated in both preclinical and clinical translational studies.

Methods

The radiolabelling procedure of Al18F-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the Al18F-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al18F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al18F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients.

Results

The radiolabelling yield of Al18F-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3–55.5 MBq/nmol. The whole body effective dose of Al18F-NOTA-FAPI was estimated to be 1.24E − 02 mSv/MBq, which was lower than several other FAPI probes (68Ga-FAPI-04, 68Ga-FAPI-46 and 68Ga-FAPI-74). In U87MG tumour-bearing mice, Al18F-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, Al18F-NOTA-FAPI showed a lower SUVmean than 2-[18F]-fluoro-2-deoxy-D-glucose (2-[18F]FDG) in most organs, especially in the liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, Al18F-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[18F]FDG in the PET/CT imaging of several patients.

Conclusion

The Al18F-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients.

Trial registration

Chinese Clinical Trial Registry ChiCTR2000038080. Registered 09 September 2020. http://www.chictr.org.cn/showproj.aspx?proj=61192

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Acknowledgements

We gratefully appreciate all of the chemists, nurses and technicians from the Department of Nuclear Medicine, Peking University Cancer Hospital, for their contributions to tracer administration and PET/CT imaging.

Funding

This work was supported by the National Natural Science Foundation of China projects No. 81871386 and 81871387, Yangfan project No. ZYLX201816, Dengfeng project No. DFL20191102, and Science Foundation of Peking University Cancer Hospital-2020–18.

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Authors and Affiliations

  1. Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China

    Shuailiang Wang & Zhi Yang

  2. Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Rd., 100142, Beijing, China

    Shuailiang Wang, Xin Zhou, Xiaoxia Xu, Jin Ding, Song Liu, Xingguo Hou, Nan Li, Hua Zhu & Zhi Yang

Authors
  1. Shuailiang Wang
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  2. Xin Zhou
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  3. Xiaoxia Xu
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  4. Jin Ding
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  5. Song Liu
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  8. Hua Zhu
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Contributions

ZY and HZ conceived and designed this research. SW was responsible for all of the experiments, data collection and analysis, and wrote the manuscript. XZ and XX were responsible for the recruitment of patients and image analysis. JD, SL and XH were involved in the preparation of radiopharmaceuticals and took part in most of the animal experiments. All of the authors participated in the revision of the article.

Corresponding authors

Correspondence to Hua Zhu or Zhi Yang.

Ethics declarations

Ethics approval

All procedures involving human participants were carried out in accordance with the Ethics Committee of Peking University Cancer Hospital (2019 KT95), and registered in Chinese Clinical Trial Registry (ChiCTR2000038080). All animal studies were performed according to a protocol approved by the Peking University Cancer Hospital Animal Care and Use Committee.

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Written informed consent was obtained from all participants included in the study.

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Not applicable.

Conflict of interest

The authors declare no competing interests.

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Wang, S., Zhou, X., Xu, X. et al. Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging. Eur J Nucl Med Mol Imaging 48, 4259–4271 (2021). https://doi.org/10.1007/s00259-021-05470-5

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