PET imaging of glutamine metabolism
L-Glutamine (Gln) is the most abundant amino acid in blood plasma. Glutamine is synthesized by glutamine synthetase from glutamate and ammonia. Glutamine has important metabolic roles in energy production and protein synthesis via TCA cycle, it acts as carrier of ammonia and as nitrogen source for synthesis of nucleotides and amino acids, and it is important in regulation of acid-base and redox homeostasis. Glutaminase converts L-glutamine to L-glutamate, and glutamate dehydrogenase produces α-ketoglutarate, which enters the TCA. In the central nervous system, L-glutamine is taken up by presynaptic neurons, and the produced L-glutamate is stored in vesicles to be used as neurotransmitter in the glutamatergic system.
Glutamine is transported into cells via many amino acid transporters, including system A, LAT1, and ASCT2.
Several cancer cell types, like most proliferating cells, are dependent on external source of glutamine and have increased glutamine transport (ASCT2/SLC1A5) and glutaminase activity (Yang et al., 2017; Zhang et al., 2017). This makes glutamine transport and metabolism an attractive target for PET tracer development (Rajagopalan and DeBerardinis, 2011; Hensley et al, 2013; Lewis et al., 2015; Venneti et al., 2015; Hassanein et al., 2016; Zhu et al., 2017). In addition to ASCT2, glutamine is transported across membranes via other transporters, too, including LAT1. Transporter specificity may differ between labelled glutamine analogues.
Normally, glutamine is consumed by the visceral organs, gut, liver, kidneys, and the brain. Skeletal muscle and adipose tissue are net producers of glutamine, and the extracellular glutamine concentration is higher than in plasma. Intracellular glutamine concentrations are much lower (Yang et al., 2017). Renal proximal tubules reabsorb all filtered glutamine (Silbernagl, 1983).
Several analogues of glutamine have been synthesized for PET imaging, including L-[5-11C]glutamine ([11C]Gln, 5-11C-(2S)-glutamine), which is chemically and biologically identical to physiological glutamine (Qu et al., 2012; Cohen et al., 2022). 11C-labelled glutamine is converted into multitude of label-carrying metabolites which will complicate the modelling (Zhu et al., 2017).
Fluorine-18 labelled glutamine analogues have been developed for clinical use, targeting glutaminolytic tumours, including (2S,4S)-4-(3-[18F]fluoropropyl)glutamine ([18F]FP-Gln) (Wu et al., 2014), and (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) (Lieberman et al., 2011; Venneti et al., 2015). 18F-labelled glutamine is not metabolized in the TCA cycle, but can be incorporated into proteins (Yang et al., 2017). Defluorination of [18F]FGln is very fast even in vitro, which may support the use of [18F]FP-Gln which has slow defluorination (Jeitner et al., 2016), but [18F]FP-Gln seems to be mostly transported into cells by LAT, and not by ASCT2 like [18F]FGln. Additionally, [18F]FP-Gln produces 18F-labelled glutamate as metabolite, which is transported into cells via system xC-.
Glutamine radiotracers have shown selective tumour uptake, enabling even delineation of gliomas, in contrast to [18F]FDG] which has high uptake in the normal brain tissue. However, the uptake of glutamine analogues is high in glutamine-consuming organs including the intestine, kidney, liver, and pancreas.
Glutamine synthetase activity
[13N]ammonia has been used to measure perfusion, but it also has shown potential in quantification of glutamate metabolism (Cooper, 2011), and specifically glutamine synthetase activity in the brain (Momosaki et al., 2015), prostate cancer (Shi et al., 2014), and glioma (He et al., 2016).
- Glutamatergic system
- Protein synthesis
Jeitner TM, Kristoferson E, Azcona JA, Pinto JT, Stalnecker C, Erickson JW, Kung HF, Li J, Ploessl K, Cooper AJL. Fluorination at the 4 position alters the substrate behavior of L-glutamine and L-glutamate: Implications for positron emission tomography of neoplasias. J Fluor Chem. 2016; 192(A): 58-67. doi: 10.1016/j.jfluchem.2016.10.008.
Shen Y, Zhang Y, Li W, Chen K, Xiang M, Ma H. Glutamine metabolism: from proliferating cells to cardiomyocytes. Metabolism 2021; 121: 154778. doi: 10.1016/j.metabol.2021.154778.
Yang L, Venneti S, Nagrath D. Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng. 2017; 19: 163-194. doi: 10.1146/annurev-bioeng-071516044546.
Zhu L, Ploessl K, Zhou R, Mankoff D, Kung HF. Metabolic imaging of glutamine in cancer. J Nucl Med. 2017; 58: 533-537. doi: 10.2967/jnumed.116.182345.
Updated at: 2022-02-04
Created at: 2015-08-26
Written by: Vesa Oikonen