Uptake of 18F-Labeled 6-Fluoro-6-Deoxy-d-Glucose by Skeletal Muscle Is Responsive to Insulin Stimulation

Alterations in glucose transport have been associated with multiple pathologic disorders, including diabetes, cancer, obesity, and neurologic and psychiatric disorders. Over the past 2 decades, the prevalence of type 2 diabetes in the United States has increased 49%, and the incidence has doubled (1–3). The incidence of obesity, which is significantly associated with diabetes (3), has also increased. An important physiologic manifestation of insulin-resistant states and diabetes is a reduction in insulin-stimulated glucose transport (4,5). Accordingly, a method that enables the measurement of glucose transport in vivo under normal and pathologic conditions will advance the understanding of the pathogenesis of insulin resistance as well as mechanisms underlying the pathophysiology of diabetes. For this purpose, we have developed 18F-labeled 6-fluoro-6-deoxy-d-glucose (18F-6FDG) as a PET tracer for the noninvasive imaging of glucose transport in vivo. Because glucose is an uncharged polar molecule that does not readily pass through cell membranes, glucose transporters (GLUTs) are necessary to facilitate the glucose transport processes. Therefore, a valid glucose transport tracer must interact with GLUTs in a manner similar to that of glucose. 18F-labeled 2-fluoro-2-deoxy-d-glucose (18F-2FDG), the most common PET radiopharmaceutical, is transported by the facilitative GLUTs. Once inside the cell, 18F-2FDG is phosphorylated and thus trapped. This phosphorylation makes it difficult to quantify the transport step alone. Moreover, 18F-2FDG is a somewhat poor substrate for the sodium-dependent glucose cotransporters (SGLTs) expressed in the kidneys; the lack of reabsorption of the tracer by the kidneys results in the high activity commonly seen in the bladder in clinical PET scans (6). To date, there has been a lack of 18F-labeled tracers that are transported as glucose but not metabolized. Perhaps the best known candidate is 18F-labeled 3-fluoro-3-deoxy-d-glucose (18F-3FDG). Halama et al. (7) evaluated the myocardial uptake of 18F-3FDG in an isolated heart preparation and found evidence that it was metabolized by hexokinase. Others observed multiple metabolic products in the brain and concluded that 18F-3FDG might be an indicator of aldose reductase activity (8,9). Moreover, Berkowitz et al. (9) reported metabolic products of 18F-3FDG appearing in the urine. In contrast, we observed negligible urinary excretion of activity after 18F-6FDG injection into rats (10). Thus, the presence of multiple metabolic products of 18F-3FDG makes it unsuitable as a tracer for the measurement of the glucose transport step. 3-O-methyl-d-glucose (3OMG), the reference compound for glucose transport, is transported but not phosphorylated, and some investigators have used 11C-labeled 3OMG (11C-3OMG) for PET (11–17). However, the 20-min half-life of 11C limits the use of 11C-3OMG only to facilities with cyclotrons. In addition, its preparation generally requires a separate cyclotron irradiation and synthesis for each experiment, and the relatively short half-life limits the duration over which its biodistribution can be observed. These factors are significant impediments to its clinical use. As detailed in our previous reports (10,18), there has been no success with iodinated and other putative glucose transport tracers that have the potential to be imaged with PET or SPECT. In particular, many of the iodinated glucose derivatives are metabolized, their transport is not responsive to insulin stimulation, or they can only be transported by specific GLUTs. Accordingly, we have pursued the use of 18F-6FDG as a marker of glucose transport (10,18). The facts that 18F-6FDG lacks a hydroxyl on carbon-6 and cannot be phosphorylated address the limitation of 18F-2FDG in tracing transport alone, and the 110-min half-life of the 18F label helps overcome the disadvantages associated with the short half-life of 11C-3OMG. In addition, in earlier studies with clone 9 cells that express GLUT1 and 3T3-L1 adipocytes that express GLUT1 and GLUT4, we showed that 3H-labeled 6FDG is transported in a manner similar to that of 3H-labeled 3OMG in response to the inhibition of oxidative phosphorylation or insulin (10); in addition, it is well transported by SGLTs in the proximal tubules of the kidneys (10). Moreover, many years ago, 3H-6FDG was shown to be transported and concentrated across intestinal sacs (19). Here we further establish the potential use of 18F-6FDG as a marker of glucose transport. The results will help in the development of this tracer and a model for quantifying the rate of glucose transport distinctly from the other steps of glucose metabolism.