(4S)-4-(3-18F-Fluoropropyl)-L-glutamate for imaging xC- transporter activity using positron emission tomography in murine models of inflammatory bowel disease

368 Objectives: System xC¯ transporter plays a role in both innate and adaptive immune systems by providing increased antioxidant capacity and balancing reactive oxygen species. (4S)-4-(3-18F-Fluropropyl)-L-glutamate ([18F]FSPG) is a tracer to image system xCˉ activity with positron emission tomography (PET). We aimed to assess xCˉ activity by [18F]FSPG PET for detection and quantitation of disease activity relative to [18F]fluorodeoxyglucose ([18F]FDG) in murine models of inflammatory bowel disease (IBD). Methods: BALB/c mice with dextran sodium sulfate (DSS)-induced IBD (n=12 IBD and 6 control), and Rag2-/-γc-/- mice with T-cell (CD4+CD45RBhigh) transferred IBD (n=11 IBD and 10 control) were studied. [18F]FSPG and [18F]FDG PET/magnetic resonance imaging (MRI) scans were obtained on two consecutive days at 60 min after i.v. administration of 7.4 MBq of each tracer at the time of IBD development. PET/MRI images were assessed visually and quantitatively with the maximum standardized uptake value (SUV). Correlation between IBD activity (disease activity index and pathologic IBD score) and SUV was calculated. Immunohistochemistry (IHC) of xCT (subunit of xCˉ transporter) was studied in mice with DSS-induced and T-cell transferred IBD models (n=3 for each IBD and control group). Results: IBD in mice with DSS-induced, and T-cell transferred IBD models were well visualized by PET/MRI with [18F]FSPG and [18F]FDG, but control mice showed no significant uptake. Quantitative analysis showed that the SUV of IBD was significantly higher in IBD mice than in control mice (DSS-induced: 2.1 ± 1.0 vs. 0.9 ± 0.5, P < 0.05; T-cell transferred, 4.5 ± 1.4 vs. 0.7 ± 0.1, P < 0.001). T-cell transferred mice had higher [18F]FSPG uptake than DSS-treated mice (P < 0.001). While SUVs for [18F]FSPG and [18F]FDG were not significantly different in DSS-treated mice, SUV for [18F]FDG was significantly higher than that of [18F]FSPG in T-cell transferred mice (P < 0.05). SUV for [18F]FSPG showed positive correlations with disease activity index (DSS-induced: ρ = 0.57, P < 0.05; T-cell transferred: ρ = 0.74, P < 0.05) and pathologic IBD score (DSS-induced: ρ = 0.65, P < 0.05; T-cell transferred: ρ = 0.74, P < 0.05). In both murine models, IHC staining showed enhanced expression of xCT in the epithelium and in the lamina propria. Conclusions: [18F]FSPG PET can detect and quantitatively assess IBD activity in murine models. Assessment of increased xCˉ transporter activity in epithelium and inflammatory cells in IBD may provide unique information of a specific pathological process during inflammation different from [18F]FDG.