F-(,)4-fluoroglutamine

Increased growth and proliferation are the typical characteristic features of cancer cells, and to maintain these processes the cells have an increased demand for energy. Adenosine triphosphate is the main source of energy in normal cells, and it is produced through the tricarboxylic acid (TCA) cycle in the mitochondria. However, in cells with a malignant phenotype, the TCA is redirected to synthesize metabolic intermediates that can be used to produce fatty acids and amino acids (aa) that are required for the growth and survival of the tumor cells (1). To meet the energy requirements of cancerous tumors, the aerobic glycolytic pathway, which uses glucose to produce energy, is upregulated and serves as the major source of energy in the tumor cells (2). Therefore, [F]-fluorodeoxyglucose ([F]-FDG), an analog of glucose that is transported into and metabolized similarly to glucose in the cell (after phosphorylation to [F]-FDG-6 phosphate it cannot be further metabolized by glycolysis and remains metabolically trapped within the cell), is often used to detect, stage, and monitor cancer therapy with positron emission tomography (PET) [PubMed]. A major drawback of PET imaging with [F]-FDG is that, in addition to tumor cells, normal cells in the brain, heart, brown adipose tissue, etc., also have high metabolic rates and utilize above-average amounts of glucose, which often leads to the generation of false positive results (2). Moreover, it is known that [F]-FDG imaging cannot distinguish between infection, inflammation, and tumors (2). There are indications that many tumors do not use the glycolytic pathway to produce energy and are consequently invisible to imaging with [F]-FDG (1). Such tumors are believed to produce sufficient energy for survival by metabolizing other nutrients such as glutamine (for details, see Koglin et al. (3)), which has the highest concentration in the blood (up to ~1 mM) among all of the aa circulating in the blood and is metabolized through the glutaminolysis pathway (1). It is believed that tumors that cannot be visualized with PET using [F]-FDG do not derive their energy through glycolysis and probably use the glutaminolysis pathway as an alternate source of energy. In a preliminary study with 9L (rat brain gliosarcoma cells) and SF188 (of human glioblastoma origin) tumor cells that are addicted to glutamine (for details, see Wise and Thompson (4)), it was shown that both cell types had a higher uptake of F-labeled (,)4-fluoroglutamine ([F]4-FGln; an analog of glutamine) than of [H]-glutamine (5). It was also observed that the uptake of [F]4-FGln by the 9L cells was inhibited by l-glutamine, which indicated that both the aa were taken up by the cells through a common transporter. On the basis of these observations, Lieberman et al. studied the biodistribution of [F]4-FGln in normal mice and rats and in mice and rats bearing xenograft tumors (1). The F-labeled compound was also evaluated for the PET detection of tumors in mice and rats bearing these lesions.