[PubMed]

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, [¹⁸F]-fluorodeoxyglucose ([¹⁸F]-FDG), an analog of glucose that is transported into and metabolized similarly to glucose in the cell (after phosphorylation to [¹⁸F]-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 [¹⁸F]-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 [¹⁸F]-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 [¹⁸F]-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 [¹⁸F]-FDG do not derive their energy through glycolysis and probably use the glutaminolysis pathway as an alternate source of energy. In a preliminary in vitro study with 9L (rat brain gliosarcoma cells) and SF188_Bcl-xL (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 ¹⁸F-labeled (2S,4R)4-fluoroglutamine ([¹⁸F]4-FGln; an analog of glutamine) than of [³H]-glutamine (5). It was also observed that the uptake of [¹⁸F]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 [¹⁸F]4-FGln in normal mice and rats and in mice and rats bearing xenograft tumors (1). The ¹⁸F-labeled compound was also evaluated for the PET detection of tumors in mice and rats bearing these lesions.

[PubMed]

The synthesis and ¹⁸F labeling of 4-FGln have been described by Lieberman et al. (1). The final labeled product had a non-decay-corrected radiochemical yield of 8.4 ± 3.4%, a radiochemical purity (RCP) of 98 ± 1%, and an optical purity of 91 ± 8% (results were derived from ten separate experiments). The specific activity of [¹⁸F]4-FGln was not reported.

The [¹⁸F]-FDG and l-[3,4-³H(N)]-glutamine ([³H]-Gln) for the in vitro cell uptake studies were purchased from commercial sources. The RCP and specific activity of [¹⁸F]-FDG were not mentioned. The RCP and specific activity of [³H]-Gln were >97% and1.11–2.22 TBq/mmol (~30–60 Ci/mmol), respectively.

[PubMed]

The uptake of [¹⁸F]4-FGln was studied in 9L and SF188 cells (these cells have an amplified c-Myc oncogene that leads to glutamine addiction and increases uptake of the aa) as described elsewhere (1). Both cell lines showed a high uptake of [¹⁸F]4-FGln, and the 9L cells showed a linear increase in the incorporation of label up to a maximum of 15.7 ± 1.0% of the initial dose per 100 μg protein content (% ID/100 μg protein) at 120 min. The SF188 cells had a different kinetics of [¹⁸F]4-FGln uptake, and the maximum uptake of ~15% ID/100 μg protein was observed at 60 min, which decreased to ~10% ID/100 μg protein at 120 min.

In another study, the uptake of [¹⁸F]4-FGln, [¹⁸F]-FDG, and [³H]-Gln was studied in SF188_Bcl-xl cells (SF188_Bcl-xl cells transfected with the B-cell lymphoma extra large outer mitochondrial transmembrane anti-apoptotic protein), and these cells showed a higher incorporation of [¹⁸F]4-FGln from 30 min to 120 min than either [¹⁸F]-FDG or [³H]-Gln (1). From this study, the investigators concluded that the high uptake of [¹⁸F]4-FGln compared to the other two tracers was most likely due to upregulation of the c-Myc gene in these cells.

The incorporation of [¹⁸F]4-FGln into protein was measured at 30 min and 120 min in 9L and SF188 cells (1). For this study, [³H]-Gln was used as a reference ligand. Both tracers showed a similar profile of incorporation into the proteins. The incorporation of [¹⁸F]4-FGln and [³H]-Gln in the 9L cells was 29% and 72% at 30 min and 120 min, respectively, and with the SF188 cells the incorporation was 12% and 62%, respectively, at the two time points.

[PubMed]

No publication is currently available.

[Disclaimers]

No information is currently available.

1.

Lieberman B.P., Ploessl K., Wang L., Qu W., Zha Z., Wise D.R., Chodosh L.A., Belka G., Thompson C.B., Kung H.F. PET Imaging of Glutaminolysis in Tumors by 18F-(2S,4R)4-Fluoroglutamine. J Nucl Med. 2011;52(12):1947–55. [PubMed: 22095958]

2.

Zhu A., Lee D., Shim H. Metabolic positron emission tomography imaging in cancer detection and therapy response. Semin Oncol. 2011;38(1):55–69. [PMC free article: PMC3075495] [PubMed: 21362516]

3.

Koglin N., Mueller A., Berndt M., Schmitt-Willich H., Toschi L., Stephens A.W., Gekeler V., Friebe M., Dinkelborg L.M. Specific PET imaging of xC- transporter activity using a (1)F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism. Clin Cancer Res. 2011;17(18):6000–11. [PubMed: 21750203]

4.

Wise D.R., Thompson C.B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–33. [PMC free article: PMC2917518] [PubMed: 20570523]

5.

Qu W., Zha Z., Ploessl K., Lieberman B.P., Zhu L., Wise D.R., Thompson C.B., Kung H.F. Synthesis of optically pure 4-fluoro-glutamines as potential metabolic imaging agents for tumors. J Am Chem Soc. 2011;133(4):1122–33. [PubMed: 21190335]