Synthesis and Preliminary Evaluation of ¹³¹I‑Labeled FAPI Tracers for Cancer Theranostics

As an excellent target for cancer theranostics, fibroblast activation protein (FAP) has become an attractive focus in cancer research. A class of FAP inhibitors (FAPIs) with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold were developed, which displayed nanomolar affinity and high selectivity. Compared with ⁹⁰Y, ¹⁷⁷Lu, ²²⁵Ac, and ¹⁸⁸Re, ²¹¹At seems to be more favored as a therapeutic candidate for FAPI tracers which have fast washout and short retention in tumor sites. Thus, the current study reported the synthesis of two FAPI precursors for ²¹¹At and ¹³¹I labeling and the preliminary evaluation of ¹³¹I-labeled FAPI analogues for cancer theranostics. FAPI variants with stannyl precursors were successfully synthesized and labeled with ¹³¹I using a radioiododestannylation reaction. Two radioactive tracers were obtained with high radiochemical purity over 99% and good radiochemical yields of 58.2 ± 1.78 and 59.5 ± 4.44% for ¹³¹I-FAPI-02 and ¹³¹I-FAPI-04, respectively. Both tracers showed high specific binding to U87MG cells in comparison with little binding to MCF-7 cells. Compared to ¹³¹I-FAPI-02, ¹³¹I-FAPI-04 exhibited higher affinity, more intracellular uptake, and longer retention time in vitro. Biodistribution studies revealed that both tracers were mainly excreted through the kidneys as well as the hepatobiliary pathway due to their high lipophilicity. In addition, higher accumulation, longer dwell time, and increased tumor-to-organ ratios were achieved by ¹³¹I-FAPI-04, which was clearly demonstrated by SPECT/CT imaging. Furthermore, intratumor injection of ¹³¹I-FAPI-04 significantly suppressed the tumor growth in U87MG xenograft mice without significant toxicity observed. The above results implied that FAP-targeted alpha endoradiotherapy (specific to ²¹¹At) should be used to treat tumors in the near future, considering the chemical similarity between iodine and astatine can ensure the labeling of the latter onto the designed FAPIs.