Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy

Purpose Fibroblast activation protein (FAP) is a pan-cancer target and now the state-of-the-art to develop radiopharmaceuticals. FAP inhibitors have been of great success in developing imaging tracers. Yet, the overly rapid clearance cannot match with the long half-lives of regular therapeutic radionuclides. Though strategies that aim to elongate the circulation of FAPIs are being developed, here we describe an innovation that uses α-emitters of short half-lives (e.g., 213 Bi) to pair the rapid pharmacokinetics of FAPIs. Methods An organotrifluoroborate linker is engineered to FAPIs to give two advantages: (1) selectively increases tumor uptake and retention; (2) facile 18 F-radiolabeling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general. Results The organotrifluoroborate linker helps to improve the internalization in cancer cells, resulting in notably higher tumor uptake while the background is clean. In FAP-expressed tumor-bearing mice, this FAPI labeled with 213 Bi, a short half-life α-emitter, exhibits almost complete suppression to tumor growth while the side effect is negligible. Additional data shows that this strategy is generally applicable to guide other α-emitters, such as 212 Bi, 212 Pb, and 149 Tb. Conclusion The organotrifluoroborate linker may be of importance to optimize FAP-targeted radiopharmaceuticals, and the short half-lived α-emitters may be of choice for the rapid-cleared small molecule-based radiopharmaceuticals.