Background: Fibroblast activation protein (FAP) is highly expressed in the stroma of various cancers, making it a promising target for positron emission tomography (PET) imaging. This study aimed to evaluate the clinical performance of ⁶⁸ Ga-labeled fibroblast activation protein inhibitor (FAPI)-46 PET/CT across multiple cancer types.

Methods: In this single-center, retrospective study, we included 22 patients (mean age 43 years, range 10-69) with histopathologically confirmed primary or metastatic cancers in whom ¹⁸ F-FDG PET/CT or conventional imaging yielded inconclusive results. All patients underwent ⁶⁸ Ga-FAPI-46 PET/CT. Scan positivity was determined by two experienced nuclear medicine physicians based on non-physiologic tracer uptake. Malignancy was confirmed by histopathology (the reference standard) or correlative imaging follow-up. Analysis was performed on both a per-patient and per-lesion basis. Tumor uptake was quantified using maximum standardized uptake value (SUV<inf>max</inf>) and tumor-to-background ratio (TBR). Statistical comparisons of SUV<inf>max</inf> and TBR between different groups were performed using Student's t-tests.

Results: A total of 115 lesions were identified and evaluated across 12 different cancer types. The highest ⁶⁸ Ga-FAPI-46 avidity (SUV<inf>max</inf>>12) was observed in sarcoma, breast cancer, and cholangiocarcinoma, while the lowest uptake (SUV<inf>max</inf><6) was found in renal cell, differentiated thyroid, and gastric cancers. Intermediate uptake (SUV<inf>max</inf> 6-12) was seen in hepatocellular, colorectal, and ovarian cancers. Due to minimal background activity (muscle and blood pool SUV<inf>max</inf><2), TBRs were high, exceeding 3-fold for intermediate and 6-fold for high-uptake tumors.

Conclusions: ⁶⁸ Ga-FAPI-46 PET/CT provides high-contrast imaging across a wide spectrum of malignancies, demonstrating particularly strong potential for visualizing tumors with prominent stromal components. These findings suggest a significant clinical role for this modality in improving tumor staging, restaging, and therapy assessment, especially in cases where ¹⁸ F-FDG PET/CT is suboptimal.