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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.
Highlights
We presented the development of several quinoline-based theranostic radiotracers, which were successfully used for tumor imaging of a multitude of different cancers, including pancreas, breast, and colon carcinoma, as well as high-grade glioblastoma [10,11]
The tumor uptake from 1 to 3 h after injection decreased by 75% for FAPI02, tumor retention was slightly prolonged with FAPI-04 (50% washout)
Chemical Modification of the FAPI Framework Resulting in Increased Fibroblast activation protein (FAP) Binding In Vitro
Summary
Fibroblast activation protein (FAP), a member of the serine protease family, is expressed in the microenvironment of more than 90% of epithelial tumors, including pancreas, colon, breast, and ENT (ear, nose, and throat) carcinomas [1]. Despite its controversial pathophysiologic role in tumor progression, overexpression of the membrane protein is associated with a poor prognosis and a fast progression of disease [2,3,4]. On this account, FAP indisputably represents an interesting target structure for imaging and the targeted delivery of therapeutically active compounds [1,5,6,7,8,9]. We presented the development of several quinoline-based theranostic radiotracers, which were successfully used for tumor imaging of a multitude of different cancers, including pancreas, breast, and colon carcinoma, as well as high-grade glioblastoma [10,11]. We aimed for further development of these FAP-targeting molecules to increase the total tumor dose while maintaining low unspecific binding to healthy tissue
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