Small-Animal SPECT/CT of the Progression and Recovery of Rat Liver Fibrosis by Using an Integrin αvβ3-targeting Radiotracer

Purpose: To assess the potential utility of an integrin alpha(v)beta(3)-targeting radiotracer, technetium 99m-PEG(4)-E[PEG(4)-cyclo(arginineglycine-aspartic acid-D-phenylalanine-lysine)](2) (Tc-99m-3PRGD2), for single photon emission computed tomography (SPECT)/computed tomography (CT) for monitoring of the progression and prognosis of liver fibrosis in a rat model. Materials and Methods: All animal experiments were performed by following the protocol approved by the institutional animal care and use committee. Tc-99m-3PRGD2 was prepared and longitudinal SPECT/CT was performed to monitor the progression (n = 8) and recovery (n = 5) of liver fibrosis induced in a rat model by means of thioacetamide (TAA) administration. The mean liver-to-background radioactivity per unit volume ratio was analyzed for comparisons between the TAA and control (saline) groups at different stages of liver fibrosis. Data were compared by using Student t and Mann-Whitney tests. Results of SPECT/CT were compared with those of ex vivo biodistribution analysis (n = 5). Results: Accumulation of Tc-99m-3PRGD2 in the liver increased in proportion to the progression of fibrosis and TAA exposure time; accumulation levels were significantly different between the TAA and control groups as early as week 4 of TAA administration (liver-to-background ratio: 32.30 +/- 3.39 vs 19.01 +/- 3.31; P = .0002). Results of ex vivo immunofluorescence staining demonstrated the positive expression of integrin alpha(v)beta(3) on the activated hepatic stellate cells, and the integrin alpha(v)beta(3) levels in the liver corresponded to the results of SPECT/CT (R-2 = 0.75, P < .0001). Tc-99m-3PRGD2 uptake in the fibrotic liver decreased after antifibrotic therapy with interferon alpha(v)beta(3) compared with that in the control group (relative liver-to-background ratio: 0.45 +/- 0.05 vs 1.01 +/- 0.05; P < .0001) or spontaneous recovery (relative liver-to-background ratio: 0.56 +/- 0.06 vs 1.01 +/- 0.05; P < .0001). Conclusion: Tc-99m-3PRGD2 SPECT/CT was successfully used to monitor the progression and recovery of liver fibrosis and shows potential applications for noninvasive diagnosis of early stage liver fibrosis. (C) RSNA, 2015