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Research ArticleTranslational

Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein

Thomas Lindner, Anastasia Loktev, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Jürgen Debus, Dirk Jäger, Walter Mier and Uwe Haberkorn
Journal of Nuclear Medicine September 2018, 59 (9) 1415-1422; DOI: https://doi.org/10.2967/jnumed.118.210443
Thomas Lindner
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Anastasia Loktev
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
2Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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Annette Altmann
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
2Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Frederik Giesel
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Clemens Kratochwil
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Jürgen Debus
4Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
5Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; and
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Dirk Jäger
6Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Walter Mier
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
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Uwe Haberkorn
1Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
2Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Abstract

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is involved in a variety of tumor-promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance, and immunosuppression. Because FAP shows low expression in most normal organs, it presents an interesting target for imaging and endoradiotherapy. In this investigation, FAP inhibitors (FAPIs) were modified and optimized for use as theranostic tracers. Methods: FAPIs based on a quinoline structure were synthesized and characterized with respect to binding, internalization, and efflux in cells expressing human and murine FAP as well as CD26. Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. Results: Of 15 synthesized FAPIs, FAPI-04 was identified as the most promising tracer for clinical application. Compared with the previously published ligand, FAPI-02, FAPI-04 showed excellent stability in human serum, higher affinity for FAP as opposed to CD26, and slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals, leading to larger areas under the curve as calculated from biodistribution experiments. Finally, PET/CT scans with 68Ga-FAPI-04 in 2 patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction in pain symptoms after therapy with a considerably low dose of 90Y-FAPI-04. Conclusion: FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.

  • oncology
  • PET
  • radiopharmaceuticals
  • FAP
  • small molecules
  • theranostic

Footnotes

  • Published online Apr. 6, 2018.

  • © 2018 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 59 (9)
Journal of Nuclear Medicine
Vol. 59, Issue 9
September 1, 2018
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Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein
Thomas Lindner, Anastasia Loktev, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Jürgen Debus, Dirk Jäger, Walter Mier, Uwe Haberkorn
Journal of Nuclear Medicine Sep 2018, 59 (9) 1415-1422; DOI: 10.2967/jnumed.118.210443

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Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein
Thomas Lindner, Anastasia Loktev, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Jürgen Debus, Dirk Jäger, Walter Mier, Uwe Haberkorn
Journal of Nuclear Medicine Sep 2018, 59 (9) 1415-1422; DOI: 10.2967/jnumed.118.210443
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Keywords

  • oncology
  • PET
  • Radiopharmaceuticals
  • FAP
  • small molecules
  • Theranostic
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