Background: Fibroblast Activation Protein (FAP) is a transmembrane protein overexpressed on cancer associated fibroblasts (CAFs), and is abundantly present in many epithelial cancers, suggesting FAP is an attractive imaging and therapeutic target. FAP-2286 is a cyclic peptide that binds to FAP and is currently being evaluated as a radioligand therapy to treat patients (pts) with FAP-positive solid tumors. The role of 68Ga-FAP-2286 as a diagnostic agent is unknown. We present an interim analysis of the ability of 68Ga-FAP-2286 to detect metastatic disease across multiple cancer types. Methods: This is a first in human Phase I/II study of 68Ga-FAP-2286 (NCT04621435) with a planned total enrollment of 65 pts across 3 cohorts: dosimetry cohort (n = 5), cohort with RECIST measurable disease (n = 30) and a cohort at risk for metastases without measurable disease (n = 30). By the cutoff date of February 12, 2022, 27 pts were enrolled (3 in cohort 1, 15 in cohort 2 and 9 in cohort 3). For each pt, the five largest lesions were included for analysis, and for each lesion, the maximum standardized uptake value (SUVmax) of the 68Ga-FAP-2286 and the size (short axis for lymph nodes) were documented. In pts who had an available FDG PET performed within 8 weeks of 68Ga-FAP-2286 PET, uptake on the two scans was compared. Results: Of the 27 enrolled pts, 9 had bladder cancer, 5 sarcoma, 4 head and neck squamous cell cancer (HNSCCA), 3 breast cancer (BC), and 3 castration resistant prostate cancer (CRPC). Most pts (89%, 24/27) had tumors positive for uptake on 68Ga-FAP-2286 PET, including 30 lesions < 1.5 cm, and 17 less than 1.0 cm. 16 pts had a paired FDG PET. In these pts, the average SUVmax on 68Ga-FAP-2286 PET was 244% higher than on FDG PET. Only two pts had higher uptake on FDG PET than on 68Ga-FAP-2286 PET (HNSCCA and DSRCT). The highest relative uptake was seen in 2 pts with BC (both 3.4 times higher on 68Ga-FAP-2286 PET); the average SUVmax in BC was 16.6. The lowest uptake on 68Ga-FAP-2286 PET was CRPC with an average SUVmax of 7.0. Sarcoma had variable uptake with one pt having an SUVmax of 4.5 (Ewing’s), while two pts had an SUVmax over 30 (both undifferentiated pleomorphic). Although sarcoma had high uptake on 68Ga-FAP-2286 PET, it was similar to FDG PET uptake across the 5 pts (ratio to FDG PET = 1.0). Conclusions: 68Ga-FAP-2286 is a promising imaging agent across cancers, although its benefit is not seen equally. BC had the highest absolute uptake and highest relative uptake compared to FDG PET; prostate cancer had the lowest uptake. Further work should be undertaken to define the settings where 68Ga-FAP-2286 PET may inform clinical decision making, and which pts may benefit from FAP-targeted radioligand therapy. Clinical trial information: NCT04621435.