Evaluation of an Integrin α(v)β(3) Radiotracer, [(18)F]F-FPP-RGD(2), for Monitoring Pharmacological Effects of Integrin α(v) siRNA in the NASH Liver.

Integrin αv is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αvβ3 positron emission tomography (PET) radiotracer, 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([18F]F-FPP-RGD2), for detecting hepatic integrin αv and function in nonalcoholic steatohepatitis (NASH) model rats using integrin αv siRNA. NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks. PET/computerized tomography imaging and quantification of integrin αv protein, serum aspartate aminotransferase, and alanine aminotransferase were performed 1 week after single intravenous injection of integrin αv siRNA. Integrin αv siRNA (0.1 and 0.5 mg/kg) dose-dependently decreased hepatic integrin αv protein concentrations in control and NASH model rats. The hepatic mean standard uptake value of [18F]F-FPP-RGD2 was decreased dose-dependently by integrin αv siRNA. The mean standard uptake value was positively correlated with integrin αv protein levels in control and NASH model rats. Serum aspartate aminotransferase and alanine aminotransferase concentrations were also decreased by siRNA injection and correlated with liver integrin αv protein expression levels in NASH model rats. This study suggests that [18F]F-FPP-RGD2 PET imaging is a promising radiotracer for monitoring hepatic integrin αv protein levels and hepatic function in NASH pathology.

Hiroyama S ，Matsunaga K ，Ito M ，Iimori H ，Morita I ，Nakamura J ，Shimosegawa E ，Abe K ... -  《-》

Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by (18)F-FPP-RGD(2) PET.

Rokugawa T ，Konishi H ，Ito M ，Iimori H ，Nagai R ，Shimosegawa E ，Hatazawa J ，Abe K ... -  《EJNMMI Research》

Quantitative evaluation of hepatic integrin α(v)β(3) expression by positron emission tomography imaging using (18)F-FPP-RGD(2) in rats with non-alcoholic steatohepatitis.

Hiroyama S ，Rokugawa T ，Ito M ，Iimori H ，Morita I ，Maeda H ，Fujisawa K ，Matsunaga K ，Shimosegawa E ，Abe K ... -  《EJNMMI Research》

Usefulness of (18)F-FPP-RGD(2) PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model.

Integrins αv are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αvβ3 imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an 18F-FPP-RGD2 PET probe in a rat model of bleomycin-induced lung fibrosis. Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using 18F-FPP-RGD2. Total distribution volume (VT) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan VT and lung pathology was assessed by Spearman's rank correlation. Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin αv protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of 18F-FPP-RGD2 rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for 18F-FPP-RGD2 kinetic analysis in the IPF-model lung. Logan VT values for 18F-FPP-RGD2 were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin αv protein expression, and oxygen partial pressure. Our findings demonstrate that the integrin αvβ3 PET probe 18F-FPP-RGD2 can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin αv of IPF-model rats. These findings support the utility of 18F-FPP-RGD2 PET imaging for the pathophysiological evaluation of pulmonary fibrosis.

Hiroyama S ，Matsunaga K ，Ito M ，Iimori H ，Tajiri M ，Nakano Y ，Shimosegawa E ，Abe K ... -  《-》

Imaging Fibrogenesis in a Diet-Induced Model of Nonalcoholic Steatohepatitis (NASH).

Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin α v β 3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin α v β 3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin α v β 3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin α v β 3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin α v β 3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin α v β 3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis.

Hartimath SV ，Boominathan R ，Soh V ，Cheng P ，Deng X ，Chong YC ，Yong FF ，Tan PW ，Han W ，Robins EG ，Goggi JL ... -  《-》