18F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model

Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-F-18-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetra hydro-2 H-pyran-2-y1)oxy)hexyl)ben zam ide (F-18-FBHGal), a new F-18-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GaIH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P <0.0001) was observed using confocal microscopy when co-incubated with 0.5 mu M of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of F-18-FBHGal in fibrosis liver (14.84 +/- 1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50 +/- 1.51 %ID/g, P <0.01) at 30 min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30 min post-injection) of hepatic fibrosis mice derived from both microPET imaging and biodistribution study were significantly lower (P <0.01) than those of normal mice. The pharmacokinetic parameters (7(1/2)alpha, T-1/2 beta, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of F-18-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that 18F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction. (C) 2012 Elsevier Ltd. All rights reserved.