Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis

Shuichi Hiroyama; Takemi Rokugawa; Miwa Ito; Hitoshi Iimori; Ippei Morita; Hiroki Maeda; Kae Fujisawa; Keiko Matsunaga; Eku Shimosegawa; Kohji Abe

doi:10.1186/s13550-020-00704-3

Quantitative evaluation of hepatic integrin α_vβ₃ expression by positron emission tomography imaging using ¹⁸F-FPP-RGD₂ in rats with non-alcoholic steatohepatitis

EJNMMI Res. 2020 Oct 7;10(1):118. doi: 10.1186/s13550-020-00704-3.

Authors

Affiliations

¹ Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan. shuichi.hiroyama@shionogi.co.jp.
² Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
³ Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
⁴ Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
⁵ Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
⁶ Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Arginine–glycine–aspartic acid (RGD); Fibrosis; Integrin; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic steatohepatitis (NASH); Positron emission tomography (PET).