Investigation of brain tumors using 18F-fluorobutyl ethacrynic amide and its metabolite with positron emission tomography

Abstract

Ying-Cheng Huang,1 Ho-Lien Huang,2 Chun-Nan Yeh,3 Kun-Ju Lin,4 Chung-Shan Yu2,51Department of Neurosurgery, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, 2Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, 3Department of Surgery, 4Department of Nuclear Medicine, Chang-Gung Memorial Hospital at Linkou, Chang Gung University, 5Institute of Nuclear Engineering and Science, National Tsing-Hua University, Hsinchu, TaiwanAbstract: To date, imaging of malignant glioma remains challenging. In positron emission tomography-related diagnostic imaging, differential tumor uptake of 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been shown to reflect the levels of cell proliferation and DNA synthesis. However, additional biomarkers for tumors are urgently required. Aberrant levels of glutathione transferase (GST) activity have been hypothesized to constitute such a novel diagnostic marker. Here, a C6 rat glioma tumor model was used to assess the ability of the positron emission tomography tracers, [18F]FLT and 18F-fluorobutyl ethacrynic amide ([18F]FBuEA), to indicate reactive oxygen species-induced stress responses as well as detoxification-related processes in tumors. Using a GST activity assay, we were able to demonstrate that FBuEA is more readily catalyzed by GST-π than by GST-α. Furthermore, we showed that FBuEA-GS, a metabolite of FBuEA, elicits greater cytotoxicity in tumor cells than in normal fibroblast cells. Finally, in vitro and in vivo investigation of radiotracer distribution of [18F]FBuEA and [18F]FBuEA-GS revealed preferential accumulation in C6 glioma tumor cells over normal fibroblast cells for [18F]FBuEA-GS but not for [18F]FBuEA.Keywords: fluorine-18, C6-glioma, molecular imaging, GST-α, glutathione transferase