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

Abstract Background Integrin αvβ3, 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....

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Main Authors: Shuichi Hiroyama, Takemi Rokugawa, Miwa Ito, Hitoshi Iimori, Ippei Morita, Hiroki Maeda, Kae Fujisawa, Keiko Matsunaga, Eku Shimosegawa, Kohji Abe
Format: Article
Language:English
Published: SpringerOpen 2020-10-01
Series:EJNMMI Research
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Online Access:http://link.springer.com/article/10.1186/s13550-020-00704-3
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spelling doaj-035d695fccbd4503b40ffd0c10a2ea952020-11-25T03:42:19ZengSpringerOpenEJNMMI Research2191-219X2020-10-0110111210.1186/s13550-020-00704-3Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitisShuichi Hiroyama0Takemi Rokugawa1Miwa Ito2Hitoshi Iimori3Ippei Morita4Hiroki Maeda5Kae Fujisawa6Keiko Matsunaga7Eku Shimosegawa8Kohji Abe9Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd.Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd.Translational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd.Research Laboratory for Development, Shionogi & Co., Ltd.Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd.Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd.Research Laboratory for Development, Shionogi & Co., Ltd.Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka UniversityDepartment of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka UniversityTranslational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd.Abstract Background Integrin αvβ3, 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 αvβ3 in a model of NASH by kinetic analysis using 18F-FPP-RGD2, an integrin αvβ3 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 αv or β3 protein expression. Results Biochemical and histological evaluation confirmed the development of NASH rats. Integrin αvβ3 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 αv and β3 protein expression. The strengths of these correlations were similar to those between SUV60–90 min and hepatic integrin αv 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 αv and β3 protein in the liver of NASH rats. These findings suggest that hepatic V T (IDIF) provides a quantitative assessment of integrin αvβ3 protein in liver.http://link.springer.com/article/10.1186/s13550-020-00704-3Non-alcoholic fatty liver disease (NAFLD)Non-alcoholic steatohepatitis (NASH)FibrosisIntegrinArginine–glycine–aspartic acid (RGD)Positron emission tomography (PET)
collection DOAJ
language English
format Article
sources DOAJ
author Shuichi Hiroyama
Takemi Rokugawa
Miwa Ito
Hitoshi Iimori
Ippei Morita
Hiroki Maeda
Kae Fujisawa
Keiko Matsunaga
Eku Shimosegawa
Kohji Abe
spellingShingle Shuichi Hiroyama
Takemi Rokugawa
Miwa Ito
Hitoshi Iimori
Ippei Morita
Hiroki Maeda
Kae Fujisawa
Keiko Matsunaga
Eku Shimosegawa
Kohji Abe
Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
EJNMMI Research
Non-alcoholic fatty liver disease (NAFLD)
Non-alcoholic steatohepatitis (NASH)
Fibrosis
Integrin
Arginine–glycine–aspartic acid (RGD)
Positron emission tomography (PET)
author_facet Shuichi Hiroyama
Takemi Rokugawa
Miwa Ito
Hitoshi Iimori
Ippei Morita
Hiroki Maeda
Kae Fujisawa
Keiko Matsunaga
Eku Shimosegawa
Kohji Abe
author_sort Shuichi Hiroyama
title Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
title_short Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
title_full Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
title_fullStr Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
title_full_unstemmed Quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18F-FPP-RGD2 in rats with non-alcoholic steatohepatitis
title_sort quantitative evaluation of hepatic integrin αvβ3 expression by positron emission tomography imaging using 18f-fpp-rgd2 in rats with non-alcoholic steatohepatitis
publisher SpringerOpen
series EJNMMI Research
issn 2191-219X
publishDate 2020-10-01
description Abstract Background Integrin αvβ3, 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 αvβ3 in a model of NASH by kinetic analysis using 18F-FPP-RGD2, an integrin αvβ3 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 αv or β3 protein expression. Results Biochemical and histological evaluation confirmed the development of NASH rats. Integrin αvβ3 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 αv and β3 protein expression. The strengths of these correlations were similar to those between SUV60–90 min and hepatic integrin αv 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 αv and β3 protein in the liver of NASH rats. These findings suggest that hepatic V T (IDIF) provides a quantitative assessment of integrin αvβ3 protein in liver.
topic Non-alcoholic fatty liver disease (NAFLD)
Non-alcoholic steatohepatitis (NASH)
Fibrosis
Integrin
Arginine–glycine–aspartic acid (RGD)
Positron emission tomography (PET)
url http://link.springer.com/article/10.1186/s13550-020-00704-3
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