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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FAP and FAPI-PET/CT in Malignant and Non-Malignant Diseases: A Perfect Symbiosis?
Katharina Dendl,Stefan A. Koerber,Clemens Kratochwil,Jens Cardinale,Rebecca Finck,Mardjan Dabir,Emil Novruzov,Tadashi Watabe,Vasko Kramer,Peter L. Choyke,Uwe Haberkorn,Frederik L. Giesel +11 more
TL;DR: Fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity as discussed by the authors.
Journal ArticleDOI
68Ga-FAPI PET/CT in Assessment of Liver Nodules in a Cirrhotic Patient.
TL;DR: Ga-FAPI PET/CT was performed in a 56-year-old cirrhotic patient with multiple liver nodules, which were suspected of hepatocellular carcinoma by contrast-enhanced magnetic resonance but were not visualized by F-FDG PET/ CT, and features suggestive of benign nodules were found.
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The Future of Nuclear Medicine as an Independent Specialty
TL;DR: It is argued that an optimistic outlook by the nuclear medicine community is crucial to the growth of the specialty and emphasize the urgent need for training adaptations.
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Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications.
Nicholas Favalli,Gabriele Bassi,Christian Pellegrino,Jacopo Millul,Roberto De Luca,Samuele Cazzamalli,Su Yang,Anika Trenner,Nour L. Mozaffari,Renier Myburgh,Mustafa Moroglu,Stuart J. Conway,Alessandro A. Sartori,Markus G. Manz,Richard A. Lerner,Peter K. Vogt,Jörg Scheuermann,Dario Neri +17 more
TL;DR: In this paper, a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids was used for ligand discovery.
Journal ArticleDOI
Albumin Binder-Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy.
TL;DR: Wang et al. as discussed by the authors developed two albumin binder-conjugated FAP-based radiotracers, TEFAPI-06 and TEF API-07, which are derived from FAPI-04, and optimized by conjugating two types of well-studied albumin binders, 4-(p-iodophenyl) butyric acid moiety (TEFAPI) and truncated Evans blue moiety, to try to overcome the above limitations at the expense of prolonging the blood circulation.
References
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The biology and function of fibroblasts in cancer
TL;DR: Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components and have a role in creating extracellular matrix structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy.
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Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
TL;DR: Through CD8+ T cell-mediated killing of tumor-associated fibroblasts, this vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma and opens a new venue for the combination of immuno- and chemotherapies.
Journal ArticleDOI
Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein
Thomas Lindner,Anastasia Loktev,Anastasia Loktev,Anastasia Loktev,Annette Altmann,Annette Altmann,Frederik L. Giesel,Clemens Kratochwil,Jürgen Debus,Jürgen Debus,Dirk Jäger,Walter Mier,Uwe Haberkorn +12 more
TL;DR: 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.
Journal ArticleDOI
68Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers.
Frederik L. Giesel,Clemens Kratochwil,Thomas Lindner,Manfred M. Marschalek,Anastasia Loktev,Wencke Lehnert,Jürgen Debus,Jürgen Debus,Dirk Jäger,Paul Flechsig,Annette Altmann,Walter Mier,Uwe Haberkorn +12 more
TL;DR: FAPI PET/CT is a new diagnostic method in imaging cancer patients in contrast to 18F-FDG, no diet or fasting in preparation for the examination is necessary, and image acquisition can potentially be started a few minutes after tracer application.
Journal ArticleDOI
A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts.
Anastasia Loktev,Anastasia Loktev,Anastasia Loktev,Thomas Lindner,Walter Mier,Jürgen Debus,Jürgen Debus,Annette Altmann,Annette Altmann,Dirk Jäger,Frederik L. Giesel,Clemens Kratochwil,Philippe Barthe,Christian Roumestand,Uwe Haberkorn,Uwe Haberkorn +15 more
TL;DR: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents.
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