PET Imaging of Glutaminolysis in Tumors by ¹⁸F-(2S,4R)4-Fluoroglutamine

Abstract

Changes in gene expression, metabolism, and energy requirements are hallmarks of cancer growth and self-sufficiency. Upregulation of the PI3K/Akt/mTor pathway in tumor cells has been shown to stimulate aerobic glycolysis, which has enabled 18 F-FDG PET tumor imaging. However, of the millions of 18 F-FDG PET scans conducted per year, a significant number of malignant tumors are 18 F-FDG PET-negative. Recent studies suggest that several tumors may use glutamine as the key nutrient for survival. As an alternative metabolic tracer for tumors, 18 F-(2S,4R)4-fluoroglutamine was developed as a PET tracer for mapping glutaminolytic tumors. Methods: A series of in vitro cell uptake and in vivo animal studies were performed to demonstrate tumor cell addiction to glutamine. Cell uptake studies of this tracer were performed in SF188 and 9L glioblastoma tumor cells. Dynamic small-animal PET studies of 18 F-(2S,4R)4-fluoroglutamine were conducted in 2 animal models: xenografts produced in F344 rats by subcutaneous injection of 9L tumor cells and transgenic mice with M/tomND spontaneous mammary gland tumors. Results: In vitro studies showed that both transformed 9L and SF188 tumor cells displayed a high rate of glutamine uptake (maximum uptake, 16% dose/100 mg of protein). The cell uptake of 18 F-(2S,4R)4-fluoroglutamine by SF188 cells is comparable to that of 3 H-L-glutamine but higher than that of 18 F-FDG. The tumor cell uptake can be selectively blocked. Biodistribution and PET studies showed that 18 F-(2S,4R)4-fluoroglutamine localized in tumors with a higher uptake than in surrounding muscle and liver tissues. Data suggest that certain tumor cells may use glutamine for energy production. Conclusion: The results support that 18 F-(2S,4R)4-fluoroglutamine is selectively taken up and trapped by tumor cells. It may be useful as a novel metabolic tracer for tumor imaging.

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

“…The biodistribution data showed normal organ uptake similar to that seen with other amino acid analogs [16][17][18][19][20][21][22]. In these reports, relatively high uptake is seen in the pancreas, and consistent with this, 5-[…”

“…18 F]fluoroglutamine showed highest uptake in pancreas at 1 hour (17.5 %ID/gm), and this progressively decreased over time (5.9 %ID/gm at 4 hours) [21]. This high uptake in the pancreas has been hypothesized due to the amino acid precursor requirement for exocrine hormone synthesis, and high protein turnover [21].…”

Preparation and Characterization of l-[5-11C]-Glutamine for Metabolic Imaging of Tumors

“…Recently, a novel series of fluorinated glutamine has been reported (21,36). We reported a glutamine analog, 18 F-(2S,4R)4-fluoroglutamine, that also was selectively taken up and trapped by tumor cells (21).…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…However, some tissues, particularly the brain, also take up large amounts of glucose, making FDG-PET ineffective in imaging brain tumors 165. 18 F-fluorinated glutamine ( 18 F-(2S,4R)4-fluoroglutamine( 18 F-FGln)) was developed as a potential tumor imaging tracer and validated in animal models 166,167 , and 18 F-FGln PET has since been evaluated clinically and shown promise in the diagnosis of glioma 168 . Importantly, in glioma 18 F-FGln accumulation does not necessarily suggest increased glutamine catabolism, as mouse orthotopic models of glioma and human patient samples show high rates of glutamine accumulation but comparatively low rates of glutamine metabolism [169][170][171] .…”