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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 68 Ga-FAP-2286 to detect primary and metastatic lesions in patients with various types of cancer, compared with 18 F-FDG and 68 Ga-FAP-2286. Methods: Sixty-four patients with 15 types of cancer underwent 68 Ga-FAP-2286 PET/CT for initial assessment or detection of recurrence. For comparison, 63 patients underwent paired 68 Ga-FAP-2286 and 18 F-FDG PET/CT and 19 patients underwent paired 68 Ga-FAP-2286 and 68 Ga-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 68 Ga-FAP-2286 was significantly higher than that of 18 F-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 68 Ga-FAP-2286 PET/CT, whereas 9 of the 46 lesions could not be visualized by 18 F-FDG PET/CT. The lesion detection rate of 68 Ga-FAP-2286 PET/CT was superior to that of 18 F-FDG PET/CT for involved lymph nodes (98% [105/107] vs. 85% [91/107], P 5 0.001) and bone and visceral metastases (95% [162/171] vs. 67% [114/171], P , 0.001). 68 Ga-FAP-2286 yielded tumor uptake and lesion detection rates similar to those of 68 Ga-FAPI-46 in a subcohort of 19 patients. Conclusion: 68 Ga-FAP-2286 is a promising FAP-inhibitor derivative for safe cancer diagnosis, staging, and restaging. It may be a better alternative to 18 F-FDG for the cancer types that exhibit low-to-moderate uptake of 18 F-FDG, which include gastric, pancreatic, and hepatic cancers. In addition, 68 Ga-FAP-2286 and 68 Ga-FAPI-46 yielded comparable clinical results.

68Ga-labeled PET tracer targeting PSMA is a promising diagnostic approach for staging and restating of prostate cancer (PCa), but cases with clinically relevant PCa and false-negative PSMA PET/CT have been reported. In this case, we reported 68Ga-PSMA, 18F-FDG, and 68Ga-FAPI PET/CT findings in a 65-year-old man with de novo metastatic PCa. 68Ga-FAPI PET/CT detected non–PSMA/FDG-avid primary PCa, consisting with multiparametric MRI findings. The subsequent histopathologic examination confirmed a Gleason 4 + 5 PCa. This case highlighted that 68Ga-FAPI PET/CT may be a useful imaging modality for primary PCa detection and localization.