(4S)-4-(3-18F-Fluoropropyl)-L-Glutamate for Imaging of xC- Transporter Activity in Hepatocellular Carcinoma Using PET: Preclinical and Exploratory Clinical Studies

(4S)-4-(3-F-18-fluoropropyl)-L-glutamate (F-18-FSPG, or BAY 949392) is a new tracer to assess system x(C)(-) transporter activity with PET. The aim of this study was to explore the tumor detection rate of F-18-FSPG, compared with that of F-18-FDG, in patients with hepatocellular carcinoma (HCC). Methods: Preclinically, in vivo HCC models of orthotopically implanted Huh7 and MH3924a cancer cells were studied with F-18-FSPG in Naval Medical Research Institute nude mice (n = 3) and August-Copenhagen Irish rats (n = 4), respectively. Clinically, 5 patients with HCC who had hyper- or isometabolic lesions on F-18-FDG PET were enrolled for evaluation of the tracer. Dynamic whole-body PET images with F-18-FSPG were acquired for up to 120 min after injection of approximately 300 MBq of F-18-FSPG. Immunohistochemical expression levels of the xCT subunit of the system x(C)(-) and CD44 of HCC were studied in 4 patients with HCC. Results: Strong tumor uptake and low background from nontarget tissue allowed excellent tumor visualization in animal models with orthotopically implanted liver tumors. F-18-FSPG PET procedures were well tolerated in all patients. F-18-FSPG PET and F-18-FDG detected lesions in 5 of 5 and 3 of 5 patients, respectively. The maximal standardized uptake values (SUV) were comparable (F-18-FSPG, 4.7 +/- 3.2; F-18-FDG, 6.1 +/- 2.9). The ratios of maximal SUV of the tumor to mean SUV of normal liver were also comparable (F-18-FSPG, 3.6 +/- 2.2; F-18-FDG, 2.7 +/- 1.3), but the mean SUV of normal liver of F-18-FSPG was significantly lower than that of F-18-FDG (P < 0.05). Two patients with HCC who showed both xCT and CD44 expression had moderate or intense accumulation of F-18-FSPG, but the remaining 2 patients with negative CD44 expression showed mild uptake. Conclusion: F-18-FSPG was successfully translated from preclinical evaluation into patients with HCC. F-18-FSPG may be a promising tumor PET agent with a high cancer detection rate in patients with HCC.