Development of novel FAP-targeted radiotracers with improved tumor retention

Abstract

Purpose: 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 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 in HT-1080-FAP tumor bearing mice. The most promising compounds were used for clinical PET imaging in a total of 8 cancer patients. Results: Compared to FAPI-04, 11 out 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 a majority of the compounds, resulting in images with higher contrast. Notably two of the novel 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 ten minutes 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 the majority of the derivatives, resulting in high contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage of healthy tissue, which may improve therapeutic outcome.