Quantitative evaluation of hepatic integrin α_vβ₃ expression by positron emission tomography imaging using...

Integrin α_vβ₃, which are expressed by activated hepatic stellate cells in non-alcoholic steatohepatitis (NASH), play an important role in the fibrosis. Recently, we reported that an RGD peptide positron emission tomography (PET) probe is useful as a predictor of hepatic fibrosis. Kinetic analysis of the RGD PET probe has been performed in tumours, but not in hepatic fibrosis. Therefore, we aimed to quantify hepatic integrin α_vβ₃ in a model of NASH by kinetic analysis using ¹⁸F-FPP-RGD₂, an integrin α_vβ₃ PET probe.

¹⁸F-FPP-RGD₂ PET/CT scans were performed in control and NASH rats. Tissue kinetic analyses were performed using a one-tissue, two-compartment (1T2C) and a two-tissue, three-compartment (2T3C) model using an image-derived input function (IDIF) for the left ventricle. We then conducted correlation analysis between standard uptake values (SUVs) or volume of distribution (V_T), evaluated using compartment kinetic analysis and integrin α_v or β₃ protein expression.

Biochemical and histological evaluation confirmed the development of NASH rats. Integrin α_vβ₃ protein expression and hepatic SUV were higher in NASH- than normal rats. The hepatic activity of ¹⁸F-FPP-RGD₂ peaked rapidly after administration and then gradually decreased, whereas left ventricular activity rapidly disappeared. The 2T3C model was found to be preferable for ¹⁸F-FPP-RGD₂ kinetic analysis in the liver. The V_{T (IDIF)} for ¹⁸F-FPP-RGD₂, calculated using the 2T3C model, was significantly higher in NASH- than normal rats and correlated strongly with hepatic integrin α_v and β₃ protein expression. The strengths of these correlations were similar to those between SUV_60-90 min and hepatic integrin α_v or β₃ protein expression.

We have demonstrated that the V_{T (IDIF)} of ¹⁸F-FPP-RGD₂, calculated using kinetic modelling, positively correlates with integrin α_v and β₃ protein in the liver of NASH rats. These findings suggest that hepatic V_{T (IDIF)} provides a quantitative assessment of integrin α_vβ₃ protein in liver.