Development of Fibroblast Activation Protein–Targeted Radiotracers with Improved Tumor Retention
Anastasia Loktev,Anastasia Loktev,Thomas Lindner,Eva Maria Burger,Annette Altmann,Annette Altmann,Frederik L. Giesel,Clemens Kratochwil,Jürgen Debus,Jürgen Debus,Frederik Marmé,Dirk Jäger,Walter Mier,Uwe Haberkorn +13 more
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In this paper, quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells.Abstract:
Cancer-associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as a theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small-animal PET imaging and biodistribution studies were performed on HT-1080-FAP tumor–bearing mice. The most promising compounds were used for clinical PET imaging in 8 cancer patients. Results: Compared with FAPI-04, 11 of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor-bearing mice. Moreover, tumor–to–normal-organ ratios were improved for most of the compounds, resulting in images with higher contrast. Notably two of the radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in cancer patients revealed high intratumoral uptake of both radiotracers already 10 min after administration but a higher uptake in oral mucosa, salivary glands, and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP binding and improved pharmacokinetics in most of the derivatives, resulting in high-contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage to healthy tissue, which may improve therapeutic outcome.read more
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68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer
Clemens Kratochwil,Paul Flechsig,Thomas Lindner,Labidi Abderrahim,Annette Altmann,Annette Altmann,Walter Mier,Sebastian Adeberg,Hendrik Rathke,Manuel Röhrich,Hauke Winter,Peter K. Plinkert,Frederik Marmé,Matthias Lang,Hans-Ulrich Kauczor,Dirk Jäger,Dirk Jäger,Jürgen Debus,Jürgen Debus,Uwe Haberkorn,Uwe Haberkorn,Frederik L. Giesel +21 more
TL;DR: The high and rather selective tumor uptake on 68Ga-FAPI PET/CT may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy.
Journal ArticleDOI
ImmunoPET: Concept, Design, and Applications
TL;DR: The latest immuno PET imaging strategies and their preclinical and clinical applications are presented and current conjugation strategies that can be leveraged to develop next-generation immunoPET probes are emphasized.
Journal ArticleDOI
Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models
Tadashi Watabe,Yuwei Liu,Kazuko Kaneda-Nakashima,Yoshifumi Shirakami,Thomas Lindner,Kazuhiro Ooe,Atsushi Toyoshima,Kojiro Nagata,Eku Shimosegawa,Uwe Haberkorn,Clemens Kratochwil,Atsushi Shinohara,Frederik L. Giesel,Frederik L. Giesel,Jun Hatazawa +14 more
TL;DR: This proof-of-concept study showed that 64Cu-FAPI-04 and 225Ac-F API-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer and will contribute to the development of a new treatment strategy.
Journal ArticleDOI
Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings
Haojun Chen,Liang Zhao,Dan Ruan,Yizhen Pang,Bing Hao,Yaqing Dai,Xiurong Wu,Guo Wei,Chunlei Fan,Jingxun Wu,Weipeng Huang,Qin Lin,Long Sun,Hua Wu +13 more
TL;DR: In patients undergoing oncological evaluation with inconclusive [ 18 F]FDG PET/CT findings, [ 68 Ga]Ga-DOTA-FAPI-04 may have a complementary role in discriminating mass lesions on conventional imaging, locating the primary site of unknown malignancy, modifying tumour staging, and detecting suspected disease recurrence.
Journal ArticleDOI
Targeting of activated fibroblasts for imaging and therapy.
Thomas Lindner,Anastasia Loktev,Anastasia Loktev,Frederik L. Giesel,Frederik L. Giesel,Clemens Kratochwil,Annette Altmann,Annette Altmann,Uwe Haberkorn,Uwe Haberkorn +9 more
TL;DR: An interesting target is the fibroblast activation protein (FAP) which is expressed in activated fibroblasts, but not in quiescent fibro Blasts, giving the opportunity to use this membrane-anchored enzyme as a target for radionuclide-based approaches for diagnosis and treatment of tumors.
References
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Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers.
Thomas Karsten Kilvær,Mehrdad Rakaee Khanehkenari,Turid Hellevik,Samer Al-Saad,Erna-Elise Paulsen,Roy M. Bremnes,Lill-Tove Busund,Tom Donnem,Inigo Martinez +8 more
TL;DR: The presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients and correlation analyses suggest Fap-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype.
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Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients.
Paul Tanswell,Pilar Garin-Chesa,Wolfgang J. Rettig,Sydney Welt,Chaitanya R. Divgi,Ephraim S. Casper,Ronald D. Finn,Steven M. Larson,Lloyd J. Old,Andrew M. Scott +9 more
TL;DR: The pharmacokinetics of antistromal mAbF19 were well defined in these two studies with different solid tumour types, and were comparable with those of other murine monoclonal antibodies that do not bind to normal tissue antigens or blood cells.
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