Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo

Abstract

Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG is ineffective in evaluating gliomas due to high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analogue 4-18F-(2S,4R)-fluoroglutamine (18F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced 18F-FGln-tumor avidity, corresponding with decreased tumor burden. 18F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where 18F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that 18F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.

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] .…”

“…Furthermore, two recent metabolomics and metabolic flux studies of primary human lung cancer showed little change in glutamine entry into the TCA cycle, and instead suggested that human lung cancer can synthesize glutamine from the TCA cycle 120,191 . Human and mouse gliomas exhibit high rates of glucose catabolism and accumulate but do not avidly metabolize glutamine 168 , and do not depend on circulating glutamine to maintain cancer growth, but instead utilize glucose to synthesize glutamine through glutamine synthetase to support nucleotide biosynthesis [169][170][171] . Hence, much more work is needed to further define the use of nutrients in vivo, to guide the selection of metabolic therapies in the clinic.…”

From Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical Application

“…This can be seen in various developments in the field where [ 18 F]AAs are developed and successfully applied as well. A concern in general when using F-18 is defluorination that has also been reported for the [ 18 F]AAs [128,129]. With respect to imaging with C-11-labeled peptides, further in-depth research is required.…”

PET for Therapy Response Assessment in Glioblastoma

“…The value of new amino acid PET tracers, such as α-11 C-methyl-tryptophan and 18 F-Fluciclovine as well as glutamine-based amino acid PET tracers has been evaluated with promising results in glioma patients in terms of tumor delineation, prognostication, and the differentiation of tumor recurrence from radiation injury (31,(118)(119)(120)(121)(122). Another interesting new PET target is the translocator protein (TSPO), a mitochondrial membrane protein highly expressed in activated microglia, macrophages, and neoplastic cells.…”