Simple SummaryThe roll-out of the novel pan-cancer tracer family, fibroblast activation protein (FAP) ligands, has opened a new avenue for the diagnosis of numerous epithelial malignancies. These ligands bind to these transmembrane proteins with enzymatic activity, which is predominantly found on the cell membranes of cancer-associated fibroblasts and regulate the interaction of tumor cells and the tumor microenvironment. The upregulation of these membrane proteins enhances tumor growth and leads to poor outcomes. The first studies with Ga-labeled FAP ligands in patients with pancreatic cancer led to very promising results. However, due to production and financial challenges of68Ga-labeling,18F-labeled FAP ligands emerge as the “diagnostic” FAP-tracer with the potential of widespread, economical use in regular healthcare. With this monocentric, prospective study, we aimed to investigate the utility of [18F]FAPI-74 PET/CT examination in patients with pancreatic cancer.AbstractBackground: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called “desmoplastic reaction”, leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. Methods: This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1–15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61–91 min) and 66.4 ± 6.3 min (range 60–76 min), respectively, after administration of 200 ± 94 MBq (range 79–318 MBq) and 235 ± 88 MBq (range 90–321 MBq), respectively. Quantification of tracer uptake was determined with SUVmaxand SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmaxof tumor lesions by the SUVmaxof adipose tissue, skeletal muscle, and blood pool. Results: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. Conclusion: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.