||PET imaging of liver fibrosis in rats with 18F-FEDAC, a radiotracer for translocator protein (18 kDa)
Hatori, Akiko ,
Yui, Joji ,
Xie, Lin ,
Kumata, Katsushi ,
Ogawa, MasanaoMing-Rong, Zhang
Objectives: Hepatic fibrosis is the wound response to the chronic hepatic injury caused by various factors (alcohol abuse, viral infection, cholestasis, etc), and progress to cirrhosis. The objective of this study was to noninvasively visualize and monitor the progression of hepatic fibrosis to cirrhosis using positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-18F-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide (18F-FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO), and to determine cellular sources enriching TSPO expression in the liver. Methods: Hepatic fibrosis in model rats induced by carbon tetrachloride (CCl4) was histologically evaluated. CCl4 (2 mL/kg, 50% olive oil) was injected intraperitoneally twice weekly for 2, 4, 6, or 8 weeks. The uptake of radioactivity in the rat livers was measured with PET after injection of 18F-FEDAC. Also immunohistochemical staining, ex vivo autoradiography, and qRT-PCR were performed to elucidate the relation among the radioactivity uptake, TSPO levels, and cellular sources enriching TSPO expression in damaged livers. Results: PET study showed the uptake of radioactivity accumulating in the livers increased significantly after 2, 4, 6, and 8 weeks CCl4 treatment (AUC0-30 min: 37.0 ± 1.1, 41.2 ± 1.4, 42.4 ± 1.4, and 44.2 ± 0.7, respectively) compared to control without treatment (29.9 ± 0.7). Immunohistochemical study exhibited TSPO expression mainly in macrophages and hepatic stellate cells (HSCs). Both macrophages and HSCs expressing TSPO increased with development of liver fibrosis. Ex vivo autoradiography and immunohistochemical staining showed good correlation between the distribution of radioactivity from 18F-FEDAC and the TSPO expression in damaged livers. The TSPO mRNA levels increased correspondingly with the liver damage levels (2, 4, 6, and 8 weeks CCl4 treatment; 2.2, 3.0, 6.5, and 4.6 fold, respectively) compared with the control group. Conclusions: PET imaging with 18F-FEDAC represented the progression of hepatic fibrosis to cirrhosis through the enhanced TSPO signals in hepatic macrophages and HSCs. A. Representative transverse PET/CT fusion images of rat livers. PET images were acquired between 0 and 30 min after injection of 18F-FEDAC to 2, 4, 6, or 8 weeks CCl4 treated and control rats. CCl4 (2 mL/kg, 50% sterile olive oil) was injected intraperitoneally for 2 times per week. The pseudocolor bar represents the level of 18F-FEDAC accumulation in the liver. B. Time-activity curves of livers. (n=4 for each group). C. Values of areas under the time-activity curves (AUC0-30 min, SUV min, mean ± SE) were calculated from the time-activity curves between 0 and 30 min. The values were increased at 2 weeks (1.2 fold), 4 weeks (1.4 fold), 6 weeks (1.4 fold), and 8 weeks (1.5 fold) of CCl4 treatment compared to control. A significant difference (p<0.05) was seen in the following comparisons, *: control versus CCl4 2, 4, 6, or 8 weeks treatment.
SNMMI 2015 Annual Meeting に発表のための参加