In recent years, quinoline-based fibroblast activation protein (FAP) inhibitors (FAPI) have shown promising results in the diagnosis of cancer and several other diseases, making them the hotspot of much productive research. This review summarizes the literature for the state-of-the-art FAPI-PET imaging for cancer diagnosis compared with fluorodeoxyglucose (FDG)-PET. We also summarize the use of FAPI-PET for therapeutic regimen improvement and fibroblast activation protein (FAP)-targeted molecule modification strategies, as well as preliminary clinical studies regarding FAP-targeted radionuclide therapy. Our qualitative summary of the literature to date can inform future research directions, medical guidelines, and optimal clinical decision-making.

PET imaging that targets fibroblast activation protein (FAP) on the surface of cancer-associated fibroblasts has yielded promising tumor diagnostic results. FAP-2286 contains cyclic peptides as FAP-binding motifs to optimize tumor retention compared with the small-molecule FAP inhibitor (FAPI) series (FAPI-04/46). The aim of this study was to evaluate the diagnostic accuracy of ⁶⁸Ga-FAP-2286 to detect primary and metastatic lesions in patients with various types of cancer, compared with ¹⁸F-FDG and ⁶⁸Ga-FAP-2286. Methods: Sixty-four patients with 15 types of cancer underwent ⁶⁸Ga-FAP-2286 PET/CT for initial assessment or detection of recurrence. For comparison, 63 patients underwent paired ⁶⁸Ga-FAP-2286 and ¹⁸F-FDG PET/CT and 19 patients underwent paired ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-FAPI-46 PET/CT. Lesion uptake was quantified as SUV_max and tumor-to-background ratio. The Wilcoxon matched-pairs signed-rank test was used to compare SUV_max between PET modalities, and the McNemar test was used to compare lesion detectability. Results: Uptake of ⁶⁸Ga-FAP-2286 was significantly higher than that of ¹⁸F-FDG in primary tumors (median SUV_max, 11.1 vs. 6.9; P < 0.001), lymph node metastases (median SUV_max, 10.6 vs. 6.2; P < 0.001), and distant metastases, resulting in improved image contrast and lesion detectability. All primary tumors (46/46) were clearly visualized by ⁶⁸Ga-FAP-2286 PET/CT, whereas 9 of the 46 lesions could not be visualized by ¹⁸F-FDG PET/CT. The lesion detection rate of ⁶⁸Ga-FAP-2286 PET/CT was superior to that of ¹⁸F-FDG PET/CT for involved lymph nodes (98% [105/107] vs. 85% [91/107], P = 0.001) and bone and visceral metastases (95% [162/171] vs. 67% [114/171], P < 0.001). ⁶⁸Ga-FAP-2286 yielded tumor uptake and lesion detection rates similar to those of ⁶⁸Ga-FAPI-46 in a subcohort of 19 patients. Conclusion:⁶⁸Ga-FAP-2286 is a promising FAP-inhibitor derivative for safe cancer diagnosis, staging, and restaging. It may be a better alternative to ¹⁸F-FDG for the cancer types that exhibit low-to-moderate uptake of ¹⁸F-FDG, which include gastric, pancreatic, and hepatic cancers. In addition, ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-FAPI-46 yielded comparable clinical results. Visual Abstract