title: (18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.
abstract: 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-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-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 0.5μM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of (18)F-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 30min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30min 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(1/2)α, T(1/2)β, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of (18)F-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that (18)F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction.
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou District, Taipei 112, Taiwan, ROC.
authors: Hao-Wen
authors: HW
authors: Kao
authors: Chuan-Lin
authors: CL
authors: Chen
authors: Wen-Yi
authors: WY
authors: Chang
authors: Jenn-Tzong
authors: JT
authors: Chen
authors: Wuu-Jyh
authors: WJ
authors: Lin
authors: Ren-Shyan
authors: RS
authors: Liu
authors: Hsin-Ell
authors: HE
authors: Wang
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000737:chemistry* / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes / Q000737:chemistry; D005690:Galactose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D056945:Hep G2 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D037263:Asialoglycoprotein Receptor; D001549:Benzamides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C037689:benzamide; D005690:Galactose