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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Molecular Imaging Identifies Fibroblast Activation Beyond the Infarct Region After Acute Myocardial Infarction.
Johanna Diekmann,Tobias Koenig,Carolin Zwadlo,Thorsten Derlin,Jonas Neuser,James T. Thackeray,Andreas Schäfer,Tobias L. Ross,Johann Bauersachs,Frank M. Bengel +9 more
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Clinical summary of fibroblast activation protein inhibitor-based radiopharmaceuticals: cancer and beyond
TL;DR: A comprehensive review of radiolabeled FAPI, including their clinical translation, is presented in order to clarify the current and potential future role of this class of molecules in nuclear medicine.
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Cardiac Fibroblast Activation in Patients Early After Acute Myocardial Infarction: Integration with MR Tissue Characterization and Subsequent Functional Outcome
Johanna Diekmann,Tobias Koenig,James T. Thackeray,Thorsten Derlin,Christoph Czerner,Jonas Neuser,Tobias L. Ross,Andreas Schaefer,Jochen Tillmanns,Johann Bauersachs,Frank M. Bengel +10 more
TL;DR: The 68Ga-FAPI PET signal does not match regional myocardial tissue characteristics as defined by CMR but is predictive of the evolution of ventricular dysfunction and may provide a novel biomarker of LV remodeling that is complementary to existing techniques.
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Theranostic Approach in Breast Cancer: A Treasured Tailor for Future Oncology.
Narges Jokar,Irina Velikyan,Hojjat Ahmadzadehfar,Seyed Javad Rekabpour,Esmail Jafari,Hong Hoi Ting,Hans-Jürgen Biersack,Majid Assadi +7 more
TL;DR: The current status of preclinical and clinical research using theranostic approach in breast cancer patients with potential to translate into conventional treatment strategies alone or in combination with other common treatments, especially in aggressive and resistant types of breast cancer are surveyed.
Posted ContentDOI
Preclinical Evaluation and Pilot Clinical Study of 18F-AlF-labeled FAPI-Tracers for PET Imaging of Cancer Associated Fibroblasts
Kongzhen Hu,Junqi Li,Lijuan Wang,Yong Huang,Yong Huang,Li Li,Shimin Ye,Yanjiang Han,Shun Huang,Hubing Wu,Jin Su,Jin Su,Ganghua Tang +12 more
TL;DR: A novel 18F-labeled FAP tracer for FAP imaging and its potential for clinical application is evaluated, suggesting that [18F]AlF-P-FAPI can be conveniently prepared, with promising characteristics in the preclinical evaluation.
References
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The biology and function of fibroblasts in cancer
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Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
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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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