Development of fibroblast activation protein-targeted radiotracers with improved tumor retention
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 radiophar...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 8, 2019
|
| In: |
Journal of nuclear medicine
Year: 2019, Volume: 60, Issue: 10, Pages: 1421-1429 |
| ISSN: | 2159-662X |
| DOI: | 10.2967/jnumed.118.224469 |
| Online Access: | Verlag, Volltext: https://doi.org/10.2967/jnumed.118.224469 Verlag: http://jnm.snmjournals.org/content/60/10/1421 
|
| Author Notes: | Anastasia Loktev, Thomas Lindner, Eva-Maria Burger, Annette Altmann, Frederik Giesel, Clemens Kratochwil, Jürgen Debus, Frederik Marmé, Dirk Jäger, Walter Mier, and Uwe Haberkorn |
| Summary: | 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. |
|---|---|
| Item Description: | Gesehen am 28.10.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2159-662X |
| DOI: | 10.2967/jnumed.118.224469 |