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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High Affinity and FAP-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake for FAP Inhibitors.
Yinwen Wang,Hongmei Yuan,Nan Liu,Sufan Tang,Yue Feng,Yang Liu,Ping Cai,Li Xia,Wenlu Zheng,Yue Chen,Zhijun Zhou +10 more
TL;DR: In this article , a range of novel FAP inhibitors derived from amino derivatives of UAMC1110, incorporating polyethylene glycol and bulky groups containing bifunctional DOTA chelators, were developed and characterized to study biodistribution properties and tumor-targeting performance in nude mice bearing U87MG tumor xenografts.
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68Ga-FAPI-04 PET Distinguishes Malignancy From 18F-FDG-Avid Colorectal Lesions
Chengfang Shangguan,Chen Yang,Zhao-Quan Shi,Ying Miao,Wangxi Hai,Yan Shen,Qing Qu,Biao Li,Jun Mi +8 more
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A novel molecular imaging probe 99m Tc-HYNIC-FAPI targeting cancer- associated fibroblasts
TL;DR: In this paper , a novel molecular probe 99m Tc-HYNIC-FAPI targeting cancer-associated fibroblasts (CAFs) in most malignant epithelial neoplasms, which is lower expressed in normal tissues, was explored.
Journal ArticleDOI
Fibroblast Activation Protein Inhibitor PET in Pancreatic Cancer.
TL;DR: In this paper , Radiolabeled fibroblast activation protein inhibitor (FAPI) has been introduced as a promising PET tracer for imaging of pancreatic cancer, which has generally but not universally yielded higher radiotracer uptake and tumor-to-background contrast than 18F-fluorodeoxyglucose PET/CT.
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Synthesis and Preclinical Evaluation of Novel 68Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging
Shreya Bendre,Hsiou-Ting Kuo,Helen Merkens,Zheng Pu Zhang,Antonio A. W. L. Wong,Francois Benard,Kuo-Shyan Lin +6 more
TL;DR: In this paper , the authors synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 and SB04028.
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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