Figure 2. Schematic illustrating key differences in brain metabolic fate of glucose and its non- metabolizable surrogate analog 2-deoxy-D-glucose (2DG) and its radiolabeled form ¹⁸F-fluoro- 2-deoxy-D-glucose (FDG).

Glucose, a key energy metabolite in the brain, is transported across the blood-brain barrier (BBB) via endothelial-specific glucose transporter-1 (GLUT1) hexose transporter. After uptake by brain cells, glucose undergoes glycolysis followed by Krebs cycle and oxidative metabolism providing the fuel for physiological brain functions through the generation of high-energy adenosine-3 phosphate (ATP) molecules, the foundation for neuronal and non-neuronal cell maintenance and the generation of neurotransmitters. On the other hand, glucose surrogate analogs 2DG and FDG, although still transported across the BBB via GLUT1 hexose transporter, cannot enter the glycolytic pathway or Krebs cycle in brain. After the initial hexokinase step, 2DG- 6P and FDG-6P get trapped in the brain, because they are not substrates for glucose-6P isomerase, which is a necessary metabolic step in the glycolytic pathway. Therefore, 2DG and FDG are not metabolized by the glycolytic pathway or Krebs cycle, do not generate any ATP energy-donor molecules in brain, and their net metabolic rate in brain is zero joules.