Evaluation of [F]F-TZ3108 for PET Imaging of Metabolic-Associated Fatty Liver Disease

Purpose: Sigma-1 receptor (Sig-1R), a chaperone that resides at the mitochondrion-associated endoplasmic reticulum (ER) membrane, is an ER stress biomarker. It is thought that ER stress plays a critical role in the progression of metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate a positron emission tomography (PET) tracer [F]F-TZ3108 targeting Sig-1R for MAFLD. Procedures: The mouse model of MAFLD was established by feeding high-fat diet (HFD) for 12 weeks. Dynamic (0–60 min) PET/CT scans were performed after intravenous injection of 2-deoxy-2[F]fluoro-D-glucose ([F]-FDG) and [F]F-TZ3108. Tracer kinetic modeling was performed for quantification of the PET/CT imaging of the liver. Post-PET biodistribution, the liver tissue western blotting (WB), and immunofluorescence (IF) were performed to compare the expression of Sig-1R levels in the organs harvested from both MAFLD and age-matched control mice. Results: The micro PET/CT imaging revealed a significantly decreased uptake of [F]F-TZ3108 in the livers of the MAFLD group compared to the healthy controls, while the uptake of [F]-FDG in the livers was not significantly different between the two groups. Based on the tracer kinetic modeling, the binding disassociate rate (k) for [F]F-TZ3108 was significantly increased in MAFLD group compared to healthy controls. The volume distribution (V), and the non-displacement binding potential (BP) revealed significantly decrease in MAFLD compared to healthy controls respectively. The post-PET biodistribution (%ID/g) of [F]F-TZ3108 in the livers of MAFLD mice was significantly reduced nearly twofold than that in the livers of control mice. WB and IF experiments further confirmed the reduction of Sig-1R expression in the MAFLD group. Conclusions: The expression of Sig-1R in the liver, measured by the PET tracer, [F]F-TZ3108, was significantly decreased in mouse model of MAFLD. The [F]F-TZ3108 PET/CT imaging may provide a novel means of visualization for ER stress in MAFLD or other diseases in vivo.