Journal of Cellular Biochemistry Supplement 39:25–35 (2002) Molecular Imaging of Regional Brain Tumor Biology A.M. Spence, 1 * M. Muzi, 2 and K.A. Krohn 2 1 Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195 2 Department of Radiology, University of Washington School of Medicine, Seattle, Washington 98195 Abstract Energy metabolism measurements in gliomas in vivo are now performed widely with positron emission tomography (PET). This capability has developed from a large number of basic and clinical science investigations that have cross fertilized one another. This article presents several areas that exemplify questions that have been explored over the last two decades. While the application of PET with [ 18 F]-2-fluoro-2-deoxyglucose (FDG-PET) has proven useful for grading and prognosis assessments, this approach is less clinically suitable for assessing response to therapy, even though results to date raise very intriguing biological questions. Integration of metabolic imaging results into glioma therapy protocols is a recent and only preliminarily tapped method that may prove useful in additional trials that target DNA or membrane biosynthesis, or resistance mechanisms such as hypoxia. There are exciting future directions for molecular imaging that will undoubtedly be fruitful to explore, especially apoptosis, angiogenesis and expression of mutations of genes, e.g., epidermal growth factor receptor, that promote or suppress cellular malignant behavior. J. Cell. Biochem. Suppl. 39: 25 – 35, 2002. ß 2002 Wiley-Liss, Inc. Key words: glioma; brain neoplasm; glucose metabolism; oxygen metabolism; PET; lumped constant; radiotherapy Energy metabolism in gliomas has been in- vestigated in the laboratory for decades, but only recently with the development of positron emission tomography (PET) has it become possible to perform non-invasive measurements in vivo in humans. More questions can now be addressed that probe the molecular events that lead to and sustain brain tumor growth. Tracers for investigating glucose and oxygen metabo- lism were among the first to be subjected to careful study. This article reviews the field of glioma energy metabolism as measured with PET and concludes with a presentation of several exciting future directions molecular imaging in gliomas will follow. Our laboratory investigates glioma energy metabolism to improve our understanding of the pathophysiology and response to therapy of these tumors and to use the new knowledge to develop better treatments. Glucose metabolism begins with transport from the serum and continues through the process of phosphoryla- tion catalyzed by hexokinase (HK), one of the most important enzymes controlling the rate of glucose utilization. The product, glucose-6- phosphate (G-6-P) is the starting compound for glycogen synthesis, for the Embden-Meyerhof pathway leading to lactate (glycolysis) or py- ruvate and entry to the tricarboxylic acid cycle, and for the pentose shunt (PS). Although malig- nant brain tumor tissue may show a respiratory quotient as low as 0.70, indicating some use of non-glucose substrates, glucose is the chief source of energy [Allen, 1972]. Isozymes of key enzymes are different in gliomas than normal brain. There is a shift to a greater proportion of HKII and a shift of lactate dehydrogenase (LDH) from LDH1 (heart tetra- mer) toward LDH5 (skeletal muscle tetramer), a change that favors lactate and NAD þ produc- production, since LDH5 is not inhibited by pyruvate [Gerhardt et al., 1967]. High lactate levels in tumors including gliomas have been well-documented. The pentose shunt is not very active in normal adult brain and accounts for only two percent of glucose utilization [Gaitonde et al., 1983]. Its flux is increased in rat glial neoplasms [Spence et al., 1997]. ß 2002 Wiley-Liss, Inc. Grant sponsor: NIH; Grant number: CA 42045. *Correspondence to: A.M. Spence, MD, Department of Neurology (356465), University of Washington, Seattle, WA 98195. Received 3 October 2002; Accepted 3 October 2002 DOI 10.1002/jcb.10406 Published online in Wiley InterScience (www.interscience.wiley.com).