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European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-12-2021 | Original Article

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

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

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 13/2021

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

Available only for authorised users

Liu R, Li H, Liu L, Yu J, Ren X. Fibroblast activation protein: a potential therapeutic target in cancer. Cancer Biol Ther. 2012;13:123–9.CrossRef

Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.CrossRef

Sánchez-Garrido MA, Habegger KM, Clemmensen C, Holleman C, Müller TD, Perez-Tilve D, et al. Fibroblast activation protein (FAP) as a novel metabolic target. Mol Metab. 2016;5:1015–24.CrossRef

Teichgräber V, Monasterio C, Chaitanya K, Boger R, Gordon K, Dieterle T, et al. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. Adv Med Sci. 2015;60:264–72.CrossRef

Chen M, Lei X, Shi C, Huang M, Li X, Wu B, et al. Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents. J Clin Invest. 2017;127:2689–701.CrossRef

Wang J, Li Q, Li X, Yuan W, Huang S, Cai S, et al. A novel FAPα-based Z-Gly-Pro epirubicin prodrug for improving tumor-targeting chemotherapy. Eur J Pharmacol. 2017;815:166–72.CrossRef

Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9:1639–47.PubMed

Wang LS, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.CrossRef

Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116:1955–62.CrossRef

10.

Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res. 2005;65:11156–63.CrossRef

11.

Jansen K, Heirbaut L, Verkerk R, Cheng JD, Joossens J, Cos P, et al. Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J Med Chem. 2014;57:3053–74.CrossRef

12.

Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59:1415–22.CrossRef

13.

Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, et al. ⁶⁸Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med. 2019;60:801–5.CrossRef

14.

Lindner T, Altmann A, Krämer S, Kleist C, Loktev A, Kratochwil C, Giesel F, Mier W, Marme F, Debus J, Haberkorn U. Design and development of ^99mTc-labeled FAPI tracers for SPECT imaging and ¹⁸⁸Re therapy. J Nucl Med. 2020;61:1507–13.CrossRef

15.

Watabe T, Liu Y, Kaneda-Nakashima K, Shirakami Y, Lindner T, Ooe K, et al. Theranostics targeting fibroblast activation protein in the tumor stroma: ⁶⁴Cu- and ²²⁵Ac-labeled FAPI-04 in pancreatic cancer xenograft mouse models. J Nucl Med. 2020;61:563–9.CrossRef

16.

Giesel FL, Kratochwil C, Lindner T, Marschalek MM, Loktev A, Lehnert W, et al. ⁶⁸Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2019;60:386–92.CrossRef

17.

Sabri S, Patrick C, Felix MM. The battle on time, money and precision: Da[18F] id vs. [68Ga]liath. Eur J Nucl Med Mol Imaing. 2020;47:2944–6.CrossRef

18.

Giesel FL, Adeberg S, Syed M, Lindner T, Jimenez LD, Mavriopoulou E, et al. FAPI-74 PET/CT using either ¹⁸F-AlF or cold-kit ⁶⁸Ga-labeling: biodistribution, radiation dosimetry and tumor delineation in lung cancer patients. J Nucl Med. 2021;62:201–7.CrossRef

19.

Toms J, Kogler J, Maschauer S, Daniel C, Schmidkonz C, Kuwert T, et al. Targeting fibroblast activation protein: radiosynthesis and preclinical evaluation of an ¹⁸F-labeled FAP inhibitor. J Nucl Med. 2020;61:1806–13.CrossRef

20.

Liu T, Liu C, Xu X, Liu F, Guo X, Li N, et al. Preclinical evaluation and pilot clinical study of Al¹⁸F-PSMA-BCH for prostate cancer PET imaging. J Nucl Med. 2019;60:1284–92.CrossRef

21.

Mentlein R, Hattermann K, Hemion C, Jungbluth AA, Held-Feindt J. Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors. Biol Chem. 2011;392:199–207.CrossRef

22.

Loktev A, Lindner T, Burger EM, Altmann A, Giesel F, Kratochwil C, et al. Development of fibroblast activation protein-targeted radiotracers with improved tumor retention. J Nucl Med. 2019;60:1421–9.CrossRef

23.

Chen H, Pang Y, Wu J, Zhao L, Hao B, Wu J, et al. Comparison of [⁶⁸Ga]Ga-DOTA-FAPI-04 and [¹⁸F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer. Eur J Nucl Med Mol Imaging. 2020;47:1820–32.CrossRef

24.

Xie Q, Liu T, Ding J, Zhou N, Meng X, Zhu H, et al. Synthesis, preclinical evaluation, and a pilot clinical imaging study of [¹⁸F]AlF-NOTA-JR11 for neuroendocrine neoplasms compared with [⁶⁸Ga]Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging. 2021. https://doi.org/10.1007/s00259-021-05249-8.CrossRefPubMed

Title: Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging
Authors: Shuailiang Wang
Xin Zhou
Xiaoxia Xu
Jin Ding
Song Liu
Xingguo Hou
Nan Li
Hua Zhu
Zhi Yang
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 13/2021
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05470-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

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