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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PET/CT versus PET/MRT bei Kopf-Hals-Tumoren
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FAP-Specific Signalling Is an Independent Diagnostic Approach in ACC and Not a Surrogate Marker of MRI Sequences
Dawn P Liew,Manuel Röhrich,Lisa Loi,Sebastian Adeberg,Mustafa Syed,Ewgenija Gutjahr,Heinz Peter Schlemmer,Frederik L. Giesel,Martin Bendszus,Uwe Haberkorn,Daniel Paech +10 more
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Optimization of detection of residual disease after neoadjuvant therapy in patients with esophageal cancer
Maria J. Valkema,Michail Doukas,Manon C.W. Spaander,Roelf Valkema,Henry C. Woodruff,J. Jan B. van Lanschot +5 more
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Development of FAPI Tetramers to Improve Tumor Uptake and Efficacy of FAPI Radioligand Therapy.
Yizhen Pang,Qiang Zhao,Jianyang Fang,Jianhao Chen,Lingxin Meng,Long Sun,Hua Wu,Zhide Guo,Qin Lin,Haojun Chen +9 more
TL;DR: In this article , the tumor-targeting characteristics of radiolabeled FAP multimers in vitro and in vivo were evaluated and compared with that of the 177Lu-FAPI dimer and monomer.
Journal ArticleDOI
Fibroblast Activation Protein Inhibitor PET/CT in Gastric Cancer
TL;DR: In this paper , the authors reported the utility and superiority of FAP inhibitor (FAPI)-PET over [18F]fluorodeoxyglucose (FDG)-PET in gastric cancers, from initial staging to recurrence detection.
References
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Journal ArticleDOI
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.
Journal ArticleDOI
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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