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Introduction <p>The adenosine monophosphate-activated protein kinase (AMPK) induces glucose uptake by increasing the expression of glucose transporter 4 (GLUT4), and [<sup>18</sup>F]Fluorodeoxyglucose (FDG) is readily transported into tissues with high GLUT4 expression. Thus, positron emission tomography with FDG (FDG-PET) could serve as an important pharmacodynamic readout of AMPK activation. In this study, the impact of treatment with the pan-AMPK activator MK-8722 on FDG uptake was evaluated in rats and Rhesus monkeys.</p> Methods <p>Rats were evaluated with FDG-PET following intravenous (IV) or oral (PO) administration of MK-8722. Rhesus monkeys were orally dosed and evaluated with FDG-PET. FDG uptake was measured in skeletal and cardiac muscle, and the incorporation rate was calculated using the Patlak graphical method.</p> Results <p>In rats, the highest IV dose of MK-8722 (5&#xa0;mg/kg) and both PO doses (4&#xa0;mg/kg and 10&#xa0;mg/kg) given 4&#xa0;h prior to FDG-PET resulted in a significant increase in forelimb skeletal muscle FDG uptake (p &lt; 0.01). In Rhesus monkeys, chronic oral administration of 10&#xa0;mg/kg MK-8722 QD resulted in significantly higher FDG uptake in bicep skeletal muscle than vehicle treatment after 2 and 4&#xa0;weeks of treatment (p &lt; 0.01), but no difference was observed after 5&#xa0;weeks of drug washout (p &gt; 0.05). FDG uptake in cardiac muscle was significantly reduced with MK-8722 treatment in rats, but no significant changes in cardiac muscle FDG uptake were measured in Rhesus monkey.</p> Conclusions <p>FDG-PET can be used as a pharmacodynamic readout for systemic pharmacological activation of AMPK for preclinical studies and potentially be extended to study humans.</p>

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AMPK Activation by MK-8722 Measured with [18F]FDG-PET Imaging in Rodents and Non-Human Primates

  • 期刊论文

  • 发表日期：

    2025年12月22日

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  • Daniel J. Rubins,
  • Xiangjun Meng,
  • Shubing Wang,
  • Hyking Haley,
  • Diane Posavec,
  • Mona Purcell,
  • Kerry Riffel,
  • Robert W. Myers,
  • Iyassu K. Sebhat,
  • Dinko Gonzalez Trotter,
  • Michael Klimas,
  • Marie Holahan

摘要

Introduction

The adenosine monophosphate-activated protein kinase (AMPK) induces glucose uptake by increasing the expression of glucose transporter 4 (GLUT4), and [18F]Fluorodeoxyglucose (FDG) is readily transported into tissues with high GLUT4 expression. Thus, positron emission tomography with FDG (FDG-PET) could serve as an important pharmacodynamic readout of AMPK activation. In this study, the impact of treatment with the pan-AMPK activator MK-8722 on FDG uptake was evaluated in rats and Rhesus monkeys.

Methods

Rats were evaluated with FDG-PET following intravenous (IV) or oral (PO) administration of MK-8722. Rhesus monkeys were orally dosed and evaluated with FDG-PET. FDG uptake was measured in skeletal and cardiac muscle, and the incorporation rate was calculated using the Patlak graphical method.

Results

In rats, the highest IV dose of MK-8722 (5 mg/kg) and both PO doses (4 mg/kg and 10 mg/kg) given 4 h prior to FDG-PET resulted in a significant increase in forelimb skeletal muscle FDG uptake (p < 0.01). In Rhesus monkeys, chronic oral administration of 10 mg/kg MK-8722 QD resulted in significantly higher FDG uptake in bicep skeletal muscle than vehicle treatment after 2 and 4 weeks of treatment (p < 0.01), but no difference was observed after 5 weeks of drug washout (p > 0.05). FDG uptake in cardiac muscle was significantly reduced with MK-8722 treatment in rats, but no significant changes in cardiac muscle FDG uptake were measured in Rhesus monkey.

Conclusions

FDG-PET can be used as a pharmacodynamic readout for systemic pharmacological activation of AMPK for preclinical studies and potentially be extended to study humans.