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

Article abstract of DOI:10.1016/j.bmc.2012.12.022

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 4-¹⁸F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide (¹⁸F-FBHGal), a new ¹⁸F-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 GalH-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 μM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of ¹⁸F-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 (T_1/2α, T_1/2β, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of ¹⁸F-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.