RT Journal Article SR Electronic T1 Molecular imaging of Nonalcoholic steatohepatitis (NASH) with Autotaxin-targeted [18F]ATX-1905 and Positron Emission Tomography JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 140 OP 140 VO 62 IS supplement 1 A1 Shao, Tuo A1 Deng, Xiaoyun A1 Liang, Steven YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/140.abstract AB 140Background: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth-factor-like lysophospholipid. Increased ATX expression has been detected in various clinical liver disease. However, little is known about its role and mode of action in nonalcoholic steatohepatitis (NASH) animal model. Here, increased ATX expression was first detected in preclinical NASH model. These results suggest that ATX pathway may be a novel therapeutic and diagnosis strategy for NASH. Molecular imaging targeting the ATX could provide a non- invasive method for evaluating the expression and the function of the ATX in the NASH, and then provide important prognostic information. In this study we aimed to evaluated whether PET imaging with radiotracers that quantify ATX activation can visualize and quantify NASH in preclinical mouse model. Methods: We employed a NASH mouse model, in which mice were initiated on either standard chow or CDAHFD (L-amino acid diet with 60 kcal% fat with 0.1% methionine without added choline) ad libitum for 14 weeks. We used an ATX-specific PET ligand [18F]ATX-1905 (2-((2-ethyl-6-(4-(2-(4-(2-fluoroethyl-1,1,2,2-d4)piperazin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile) to evaluate hepatic ATX PET signal and uptake in the NASH mouse models. We performed HE, oil red O and Sirius red staining to assess liver steatosis and liver fibrosis, immunofluorescence and RT-PCR to assess ATX protein and gene expression in the NASH liver. Results: HE, oil red o and Sirius red staining showed a significant steatosis and liver fibrosis, indicating an advanced NASH (Fig. 1A). 60 min [18F]ATX-1905 PET preformation demonstrated high uptake in NASH liver compared with controls. The accumulation of radioactivity in the livers increased significantly in all treatment groups compared with that of normal controls (Fig. 1 B). Real time PCR confirmed the PET imaging finding that ATX expression was upregulated in 14 weeks NASH animal models compared with control (Fig. 1C). Immunofluorescence stained ATX (green), collagen marker Cola1 (red) and DAPI (blue) shown that ATX expression was increased with collagen development in NASH, which consisted PET imaging and RT-PCR results (Fig. 1D). To our knowledge, this is the first study that systematically validates TAX/PET imaging in NASH disease by performing a spatially precise correlative analysis of PET imaging, histopathology, ATX expression in preclinical rodent models Conclusions: [18F]ATX-1905 is a promising candidate for noninvasive imaging of NASH in the ATX signaling pathway.