6-Deoxy-6-[F]fluoro-D-fructose

The phosphorylation of glucose, an initial and important step in cellular metabolism, is catalyzed by hexokinases (HKs) (1). There are four HKs in mammalian tissues. HKI, HKII, and HKIII have molecular weights of ~100,000 each. HKI is found mainly in the brain. HKII is insulin-sensitive and is found in adipose and muscle cells. HKIV, also known as glucokinase, has a molecular weight of 50,000 and is specific to the liver and pancreas. Most brain HK is bound to mitochondria, enabling coordination between glucose consumption and oxidation. Tumor cells are known to be highly glycolytic because of increased expression of glycolytic enzymes and HK activity (2), which is detected in tumors from patients with lung, gastrointestinal, and breast cancer. The HKs, by converting glucose to glucose-6-phosphate, help maintain the downhill gradient that results in the transport of glucose into cells through the facilitative glucose transporters (GLUT1-13) (3). GLUT4 and HKII are the major transporter and HK isoform in skeletal muscle, heart, and adipose tissue, wherein insulin promotes glucose utilization. HKIV is associated with GLUT2 in liver and pancreatic β cells. 2-Deoxy-d-glucose (2DG) was first developed to inhibit glucose utilization by cancer cells (4). HKs phosphorylate 2DG to 2-DG-6-phosphate, which inhibits phosphorylation of glucose. 2-[F]Fluoro-2-deoxy-d-glucose ([F]FDG) was later developed for molecular imaging studies (5). FDG is moved into cells by glucose transporters (GLUT1 and GLUT3) and is then phosphorylated by HK to FDG-6-phosphate. FDG-6-phosphate cannot be metabolized further in the glycolytic pathway and remains within the cells. Tumor cells do not contain a sufficient amount of glucose-6-phosphatase to reverse the phosphorylation. The elevated rates of glycolysis and glucose transport in many types of tumor cells and activated cells enhance the uptake of FDG in these cells relative to other normal cells. Positron emission tomography (PET) with [F]FDG has been used to assess alterations in glucose metabolism in brain, cancer, cardiovascular diseases, Alzheimer’s disease and other central nervous system disorders, and infectious, autoimmune, and inflammatory diseases (6-11). Overall, [F]FDG PET showed 76%–89% sensitivity and 73%–80% specificity for the detection of primary breast cancer (12). Several clinical studies showed that 28%–47% of breast tumor samples were negative for GLUT1 (13, 14). The low or absent tumor expression of GLUT1 seems to account for the low sensitivity of [F]FDG PET in detecting these breast tumors. High-affinity fructose transporter GLUT5 was found to be overexpressed in 37% of breast tumor samples (13). 6-Deoxy-6-fluoro-D-fructose (6-FDF) is a substrate for GLUT5, whereas FDG is not (15). Wuest et al. (16) have evaluated 6-deoxy-6-[F]fluoro-D-fructose (6-[F]FDF) as a PET tracer for imaging GLUT5 expression.