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000147192 0247_ $$2ISSN$$a1535-5667
000147192 0247_ $$2ISSN$$a2159-662X
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000147192 1001_ $$0P:(DE-He78)b92647c18492ca0d83530e3e93821495$$aLoktev, Anastasia$$b0$$eFirst author
000147192 245__ $$aDevelopment of Fibroblast Activation Protein-Targeted Radiotracers with Improved Tumor Retention.
000147192 260__ $$aNew York, NY$$bSoc.$$c2019
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000147192 520__ $$aCancer-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.
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000147192 7001_ $$aLindner, Thomas$$b1
000147192 7001_ $$aBurger, Eva-Maria$$b2
000147192 7001_ $$0P:(DE-He78)5f322a4feb2548d8312f781f80718b3c$$aAltmann, Annette$$b3$$udkfz
000147192 7001_ $$aGiesel, Frederik$$b4
000147192 7001_ $$aKratochwil, Clemens$$b5
000147192 7001_ $$0P:(DE-He78)8714da4e45acfa36ce87c291443a9218$$aDebus, Jürgen$$b6$$udkfz
000147192 7001_ $$aMarmé, Frederik$$b7
000147192 7001_ $$aJäger, Dirk$$b8
000147192 7001_ $$aMier, Walter$$b9
000147192 7001_ $$0P:(DE-He78)13a0afba029f5f64dc18b25ef7499558$$aHaberkorn, Uwe$$b10$$eLast author$$udkfz
000147192 773__ $$0PERI:(DE-600)2040222-3$$a10.2967/jnumed.118.224469$$gVol. 60, no. 10, p. 1421 - 1429$$n10$$p1421 - 1429$$tJournal of nuclear medicine$$v60$$x2159-662X$$y2019
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