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Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013

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

Abstract

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy.

Methods

Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer.

Results

The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection.

Conclusion

Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

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Acknowledgements

The authors acknowledge the staff of the Department of Nuclear Medicine, Xiangya Hospital, for their help in the first-in-human study. The authors thank Professor Haojun Chen (Xiamen University) for providing HT-1080-FAP and HT-1080 cell lines.

Funding

This study was supported by the Ministry of Education, Singapore, under the Academic Research Fund Tier 1 FY2022 (NUHSRO/2022/093/T1/Seed-Sep/06), the National University of Singapore Start-up Grant (NUHSRO/2021/097/Startup/13; NUHSRO/2020/133/Startup/08, NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine), Shandong Provincial Natural Science Foundation (ZR2022MH099), National Medical Research Council (MOH-001334-00, MOH-001254-00, MOH-001388–00, MOH-001041, CG21APR1005), Singapore Ministry of Education (MOE-000387–00), and National Research Foundation (NRF-000352–00).

Author information

Author notes

  1. Yue Tan and Jian Li contributed equally to this work. .

Authors and Affiliations

  1. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore

    Yue Tan, Tianzhi Zhao, Vivianne Jakobsson, Xiaoyuan Chen & Jingjing Zhang

  2. Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, People’s Republic of China

    Jian Li, Ming Zhou, Kehuang Liu, Shijun Xiang & Yongxiang Tang

  3. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore

    Tianzhi Zhao, Vivianne Jakobsson, Xiaoyuan Chen & Jingjing Zhang

  4. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Tianzhi Zhao, Vivianne Jakobsson, Xiaoyuan Chen & Jingjing Zhang

  5. Department of Nuclear Medicine, The First Affiliated Hospital of Shandong Second Medical University, Weifang, China

    Pengfei Xu

  6. Departments of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore

    Xiaoyuan Chen

  7. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore

    Xiaoyuan Chen

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  1. Yue Tan
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Corresponding authors

Correspondence to Pengfei Xu, Xiaoyuan Chen or Jingjing Zhang.

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Ethical approval was obtained from the Medical Ethics Committee of Xiangya Hospital, Central South University (Ethics Approval No. 202106053), and this study was conducted in accordance with the principles of the Declaration of Helsinki.

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Tan, Y., Li, J., Zhao, T. et al. Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06703-z

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