[18F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

Abstract

BackgroundMitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [18F]-BMS-747158-02 (18F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of 18F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with 18F-BMS were performed after 1 and 2 weeks of the MCD diet. 18F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed.ResultsIn control mice, hepatic 18F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of 18F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet.ConclusionsThe present study demonstrated that 18F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.

Sensitive and early detection of mitochondrial dysfunction in the liver of NASH model mice by PET imaging with 18F-BCPP-BF

“…At this stage, mild steatosis and inflammation without ballooning were observed upon histopathological examination. A similar finding of early changes in hepatic mitochondrial function in mice on an MCD was recently reported using 18 F-BMS-747158-02, another PET probe for MC-I, although in that study, the diet period was only 2 weeks [ 27 ]. In that study, both liver uptake of 18 F-BMS-747158-02 and MC-I activity were measured in liver homogenate, and a high correlation was found between hepatic 18 F-BMS-747158-02 uptake and MC-I activity.…”

Parathyroid Imaging: Past, Present, and Future

“…18 F-flurpiridaz ( 18 F-BMS, 18 F-BMS-747158-02) is under phase 3 clinical investigation for myocardial perfusion imaging. 18 F-flurpiridaz has shown promise in imaging mitochondria in other organs, such as liver (197), and has the potential to become an important parathyroid imaging agent (166).…”

Automated Synthesis of 18F-BCPP-EF {2-tert-Butyl-4-Chloro-5-{6-[2-(2[18F]fluoroethoxy)-Ethoxy]-Pyridin-3-ylmethoxy}-2H-Pyridazin-3-One for Imaging of Mitochondrial Complex 1 in Parkinson’s Disease

“…The University of Michigan PET Center conducted work with 11 C-labeled derivatives of rotenone in the past ( Charalambous et al, 1995a , b ; Kilbourn et al, 1997 ; Snyder et al, 1999 ), but these agents were not widely used, likely because of toxicity considerations. More recently, a pyridazinone analog, ( 18 F)BMS-747158-01 (Flurpiridaz), which advanced to clinical trials as a myocardial perfusion imaging agent ( Sattler et al, 2014 ), showed inhibitory activity for MC-1 function ( Rokugawa et al, 2017 ). Studies with the agent demonstrated high uptake and long retention not only in the heart ( Werner et al, 2019 ), but also in the brain.…”