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Effect of Solute Structure on Transport of Radiotracers
Published in Lelio G. Colombetti, Biological Transport of Radiotracers, 2020
The use of 18FDG as in vivo method for measuring regional glucose metabolism, especially in the brain, was stimulated by the work of Sokoloff and Reivich who used 14C 2-deoxy-glucose and quantitative autoradiography to measure glucose metabolism in the brain.10 When the hydroxyl group at C-2 of the glucose molecule is replaced by hydrogen, the deoxyglucose serves as a substrate to measure the hexokinase reaction because the 2-deoxy-D-glucose-6-phosphate (14C-DG-6-P) does not undergo further steps in the glycolysis cycle, but is metabolically trapped.11 The same principle of metabolic trapping applies to 18FDG-6-P.12,13 The FDG is readily transported across the cell membrane, but 18FDG-6-P is not transported back across the cell membrane, nor is it utilized in glucose metabolism beyond the phosphorylation step. Further, no detectable glucose-6-phosphatase activity was present in the heart or brain when hexokinase activity was high and at pH 6.59 The 18FDG-6-P remains trapped in the heart and brain, but 18FDG is rapidly removed from the other organs by excretion into the urine.
11C, 13N, and 15O Tracers
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Roy S. Tilbury, Alan S. Gelbard
Some of the mechanisms involved in the use of short-lived positron emitting labeled tracers are: metabolic trapping, enzyme interactions, receptor binding, and pH changes. An example of metabolic trapping is the use of labeled 2-deoxyglucose or analogues of it which follow the biochemical pathway of metabolism of glucose, become trapped as 2-deoxyglucose-6-phosphate, and cannot be metabolized further.4 The paper by Kung and Blau5 gives examples of agents used to indicate changes in pH in tissue. Labeled steroids are indicators of estrogen receptors and labeled dopiate or opiate agonists or antagonists would be useful for indicating the location and specificity of these receptors.
In Vivo Measurement of Transport and Metabolic Processes Using Radiotracers *
Published in Lelio G. Colombetti, Principles of Radiopharmacology, 1979
Brian M. Gallagher, Joanna S. Fowler, Robert R. MacGregor, Richard M. Lambrecht, Alfred P. Wolf, Elizabeth J. Crawford, Morris Friedkin
Numerous workers have attempted to measure the rates of glucose metabolism by a variety of tissues and utilizing a variety of different approaches. The use of 2-deoxy-D-glucose (an analog of D-glucose in which the hydroxyl group at carbon 2 was replaced by a hydrogen atom) as a substrate for the enzyme hexokinase, the first reaction for entry of exogenous glucose into glycolysis, “isolates the hexokinase reaction” in that the hexose phosphate formed is “metabolically trapped” intracellularly.24 This property arises from the fact that the membrane permeability of hexose phosphates is quite low,25 and that 2-deoxy-D-glucose-6-phosphate is a relatively poor substrate for subsequent metabolic steps.26 This property of metabolic trapping has been utilized in exploring many aspects of carbohydrate metabolism. Sokoloff and co-workers27–29 have developed an elegant method for the measurement of the rates of glucose consumption in various structural and functional components of the brain in vivo using 14C-2-deoxy-glucose and quantitative autoradiography. Unfortunately, this technique is limited in use to experimental animals as sacrifice of the animal is necessary to determine the distribution of radioactivity in the brain sections. An extension of this method applicable to in vivo measurement of glucose utilization utilizing a suitably labeled 2-deoxy-D-glucose analog would allow the measurement of regional glucose metabolism in man in vivo. 11C-glucose has already been utilized for similar studies with emission tomography.30,31 The in vivo demonstration of metabolic trapping, however, required that 2-deoxy-glucose be labeled with a β+ emitting nuclide which would not significantly alter its biochemical characteristics. The use of 18F as a label at C-2 was chosen since the hexokinase reaction is relatively insensitive to structural modification at this position,32 the C-F bond is quite strong resulting in a biologically stable label, and the physical decay properties of 18F for radiotracer synthesis and patient dosimetry are most convenient.
LC-MS/MS based detection and characterization of covalent glutathione modifications formed by reactive drug of abuse metabolites
Published in Xenobiotica, 2019
R. Allen Gilliland, Carolina Möller, Anthony P. DeCaprio
Metabolic trapping assays have been widely employed to study these possibly harmful products in vitro, particularly in pharmaceutical development where there is a need to identify the potential for reactive metabolite production in candidate drugs (Thompson et al., 2011; Yamaoka & Kitamura, 2015). Such assays are designed to mimic Phase I and II metabolic processes in human cells (Evans et al., 2004). When a metabolic assay is used for the purpose of examining reactive metabolite formation, a trapping agent must be added as a target for covalent modification (Meneses-Lorente et al., 2006). Trapping agents are typically any one of numerous, primarily nucleophilic and generally small, molecules that can bind covalently to reactive intermediates, preventing further metabolism and preserving the structure of the otherwise unstable compound (Schneider & DeCaprio, 2013). Examples of trapping agents used in these assays include glutathione (GSH) (Schadt et al., 2015; Yamaoka & Kitamura, 2015), N-acetylcysteine (Schneider & DeCaprio, 2013), and cyanide (Evans et al., 2004).