Development of fibroblast activation protein-targeted radiotracers with improved tumor retention

• Verfasst von: Loktev, Anastasia [VerfasserIn]
• Verfasst von: Lindner, Thomas [VerfasserIn]
• Verfasst von: Altmann, Annette [VerfasserIn]
• Verfasst von: Giesel, Frederik L. [VerfasserIn]
• Verfasst von: Kratochwil, Clemens [VerfasserIn]
• Verfasst von: Debus, Jürgen [VerfasserIn]
• Verfasst von: Marmé, Frederik [VerfasserIn]
• Verfasst von: Jäger, Dirk [VerfasserIn]
• Verfasst von: Mier, Walter [VerfasserIn]
• Verfasst von: Haberkorn, Uwe [VerfasserIn]
• Titel: Development of fibroblast activation protein-targeted radiotracers with improved tumor retention
• Verf.angabe: Anastasia Loktev, Thomas Lindner, Eva-Maria Burger, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Jürgen Debus, Frederik Marmé, Dirk Jäger, Walter Mier, and Uwe Haberkorn
• E-Jahr: 2019
• Jahr: March 8, 2019
• Umfang: 9 S.
• Teil: volume:60
• Teil: year:2019
• Teil: number:10
• Teil: pages:1421-1429
• Teil: extent:9
• Fussnoten: Gesehen am 28.10.2019
• Titel Quelle: Enthalten in: Journal of nuclear medicine
• Ort Quelle: New York, NY : Soc., 1964
• Jahr Quelle: 2019
• Band/Heft Quelle: 60(2019), 10, Seite 1421-1429
• ISSN Quelle: 2159-662X
• ISSN Quelle: 1535-5667
• DOI: doi:10.2967/jnumed.118.224469
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: FAP inhibitor
• Sach-SW: fibroblast activation protein
• Sach-SW: PET/CT
• Sach-SW: theranostics
• Sach-SW: tracer development
• K10plus-PPN: 1680065203

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.