Development of a novel PET tracer 68Ga-NOTA-KS for assessment of hepatic functional reserve in animal models of liver cirrhosis

초록

Introduction: The preoperative assessment of hepatic functional reserve is a crucial factor for successful liver surgery to reduce postoperative mortality and morbidity. However, conventional methods including the Child-Pugh classification, the model for end-stage liver disease (MELD), and the indocyanine green (ICG) clearance are the indirect methods of measuring hepatic functional reserve, which often lead to inaccurate assessment. Asialoglycoprotein receptors are expressed on normal hepatocytes of mammals and a novel synthetic compound KS was designed to bind specifically to asialoglycoprotein receptors. Thus, 68Ga-labeled KS could be suitable for visualization of asialoglycoprotein receptors in the liver by using positron emission tomography (PET) and could directly reflect the hepatic functional reserve. Here, we investigate whether a novel PET tracer 68Ga-labeld KS could reflect the hepatic functional reserve in rats with liver cirrhosis. Methods: KS was synthesized by conjugation of α-lactose to human serum albumin (HSA) through the reductive amination approach. Synthesized KS was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-NOTA) and labeled with 68Ga. Liver cirrhosis animal models were induced by an intraperitoneal injection of thioacetamide (TAA, 300 mg/kg) three times a week for 4 weeks using the male Sprague-Dawley rat. Images were acquired after injection of 68Ga-NOTA-KS in the rat tail vein before sacrifice. The liver uptake value (LUV) of 68Ga-NOTA-KS was calculated as the whole liver uptake divided by the heart uptake at different time-points after tracer injections. Histological-, and molecular analyses were performed on harvested liver. Results: Functional hepatocyte imaging was successfully visualized by using 68Ga-NOTA-KS PET/CT in live animals. Furthermore, LUV of 68Ga-NOTA-KS was significantly decreased in rats with liver cirrhosis, compared to normal rats. Among the LUVs on variable time points, LUV at 15 min after tracer injection showed the excellent correlation with the severity of liver cirrhosis. Conclusions: 68Ga-NOTA-KS PET/CT could reflect the hepatic functional reserve in liver cirrhosis rat model. Thus, LUV assessed by 68Ga-NOTA-KS PET/CT could serve as a direct surrogate marker of hepatic functional reserve.