[18F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis

Background & Aims: The vitronectin receptor integrin alpha v beta 3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin alpha v beta 3 could provide a non-invasive method for evaluating the expression and the function of the integrin alpha v beta 3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [F-18]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis. Methods: PET with [F-18]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin alpha v beta 3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl4] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin alpha v beta 3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings. Results: Fibrotic mouse livers showed enhanced [F-18]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin alpha v beta 3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin alpha v beta 3 and its signaling complex were higher in CCl4 and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings. Conclusions: Imaging hepatic integrin alpha v beta 3 with PET and [F-18]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis. Lay summary: Integrin alpha v beta 3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [F-18]-Alfatide, binds to integrin alpha v beta 3 with high affinity and specificity. [F-18]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.