Thymidine phosphorylase imaging probe for differential diagnosis of nonalcoholic steatohepatitis

Abstract

Purpose Non-alcoholic fatty liver disease (NAFLD) comprises simple steatosis (SS), which has a low risk of mortality, and non-alcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma. Because differentiation between NASH and SS is the most important issue in the diagnosis of NAFLD, the establishment of noninvasive diagnostic methods is urgently needed. In this study, we evaluated the potential of [¹²³I]IIMU, a thymidine phosphorylase (TYMP) targeted SPECT imaging probe, for differential diagnosis of NAFLD in a preclinical animal model. Procedures SS and NASH mice were prepared by feeding db/db mice with a standard diet and a methionine/choline-deficient diet, respectively. Control mice were prepared by feeding m/m mice with a standard diet. TYMP expression in the liver was evaluated by RT-PCR, western blotting, and immunohistochemistry. The biodistribution of [¹²⁵I]IIMU in the three model mice was evaluated at 30 min post-injection. SPECT/CT imaging studies of the three model mice were performed 30 min after injection of [¹²³I]IIMU. Results Hepatic TYMP expression level was the highest in the SS mice and the lowest in the NASH mice at both mRNA and protein levels. The immunohistochemistry experiment showed a patchy distribution of TYMP only in the liver of NASH mice. In the biodistribution study, the hepatic accumulation of [¹²⁵I]IIMU was the highest in the SS mice and the lowest in the NASH mice. The SPECT/CT imaging study showed similar results to the biodistribution experiment. Conclusion Hepatic TYMP expression level may serve as a promising imaging biomarker for differential diagnosis of SS and NASH. SPECT imaging using [¹²³I]IIMU potentially provides a novel noninvasive diagnostic method to differentiate NASH and SS.