1,4,52-Deoxy-D-glucose (2DG) is a known surrogate molecule that is useful for inferring glucose uptake and metabolism. Although 13 C-labeled 2DG can be detected by nuclear magnetic resonance (NMR), its low sensitivity for detection prohibits imaging to be performed. Using chemical exchange saturation transfer (CEST) as a signal-amplification mechanism, 2DG and the phosphorylated 2DG-6-phosphate (2DG6P) can be indirectly detected in 1 H magnetic resonance imaging (MRI). We showed that the CEST signal changed with 2DG concentration, and was reduced by suppressing cerebral metabolism with increased general anesthetic. The signal changes were not affected by cerebral or plasma pH, and were not correlated with altered cerebral blood flow as demonstrated by hypercapnia; neither were they related to the extracellular glucose amounts as compared with injection of D-and L-glucose. In vivo 31 P NMR revealed similar changes in 2DG6P concentration, suggesting that the CEST signal reflected the rate of glucose assimilation. This method provides a new way to use widely available MRI techniques to image deoxyglucose/glucose uptake and metabolism in vivo without the need for isotopic labeling of the molecules. Keywords: 2-deoxyglucose; glucose; glucoCEST; magnetic resonance imaging; metabolism
INTRODUCTIONThe rate of glucose uptake and its conversion into subsequent metabolites are important biomarkers of cellular function. Since the seminal work of Sokoloff et al, 1 isotopically labeled 2-deoxy-Dglucose (2DG) has been established as a way to measure glucose metabolism; this is based on the observation that 2DG enters cells by the same transporters as glucose (e.g., mostly GLUT-1 and GLUT-3 in the brain). It is phosphorylated by hexokinase into 2DG-6-phosphate (2DG6P) but only minimally metabolized further via glucose-6-phosphate dehydrogenase in the oxidative pentose phosphate pathway, and glucose-6-phosphate isomerase in the glycolytic pathway, because of the lack of a hydroxyl group on carbon atom 2 (C2). As the amount of glucose-6-phosphatase that catalyzes the hydrolysis of 2DG6P to 2DG is low in mammalian brain, and having low membrane permeability 2DG6P becomes trapped in brain cells for many hours.2 By quantifying the amount of 2DG and 2DG6P, the glucose metabolic rate can be estimated via compartmental modeling.