Radiosynthesis and pharmacokinetics of [(18)F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

PURPOSE: Bufalin, the main component of a Chinese traditional medicine chansu, shows convincing anticancer effects in a lot of tumor cell lines. However, its in vivo behavior is still unclear. This research aimed to evaluate how bufalin was dynamically absorbed after intravenous injection in animal models. We developed a radiosynthesis method of [(18)F]fluoroethyl bufalin to noninvasively evaluate the tissue biodistribution and pharmacokinetics in hepatocellular carcinoma-bearing mice. METHODS: [(18)F]fluoroethyl bufalin was synthesized with conjugation of 18F-CH(2)CH(2)OTs and bufalin. The radiochemical purity was proved by the radio-high-performance liquid chromatography (HPLC). The pharmacokinetic studies of [(18)F]fluoroethyl bufalin were then performed in Institute of Cancer Research (ICR) mice. Furthermore, the biodistribution and metabolism of [(18)F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing nude mice were studied in vivo by micro-positron emission tomography (micro-PET). RESULTS: The radiochemical purity (RCP) of [(18)F]fluoroethyl bufalin confirmed by radio-HPLC was 99%±0.18%, and [(18)F]fluoroethyl bufalin showed good in vitro and in vivo stabilities. Blood dynamics of [(18)F]fluoroethyl bufalin conformed to the two compartments in the ICR mice model. The pharmacokinetic parameters of [(18)F]fluoroethyl bufalin were calculated by DAS 2.0 software. The area under concentration–time curve (AUC(0–t)) and the values of clearance (CL) were 540.137 μg/L·min and 0.001 L/min/kg, respectively. The half-life of distribution (t(1/2)(α)) and half-life of elimination (t(1/2)(β)) were 0.693 and 510.223 min, respectively. Micro-PET imaging showed that [(18)F]fluoroethyl bufalin was quickly distributed via the blood circulation; the major tissue biodistribution of [(18)F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing mice was liver and bladder. CONCLUSION: [(18)F]fluoroethyl bufalin was accumulated rapidly in the liver at an early time point (5 min) post injection (pi) and then declined slowly, mainly through both the hepatic pathway and the renal pathway. Our study showed the biodistribution of [(18)F]fluoroethyl bufalin in micro-PET images and provided visible information for demonstrating the bioactivities of bufalin.