PET imaging of xC- transporter
The antiporter system xC- is a heterodimeric Na+-independent but Cl--dependent transporter at the plasma membrane that mediates the cellular uptake of L-cystine in exchange for intracellular L-glutamate (Bannai, 1986, Sato et al., 1999). It is composed of a light chain, xCT (SLC7a11), and a heavy chain, 4F2hc (SLC3A2). System xC- can work both ways, depending on the demand.
Intracellular cystine can be reduced to two molecules of cysteine. Cysteine is the rate-limiting substrate in glutathione (GSH) synthesis. GSH is an important intracellular antioxidant, limiting the amount of reactive oxygen species (ROS), and xC- antiporter also maintains the cysteine-cystine redox cycle extracellularly.
Statin treatment increases ROS in skeletal muscle, which leads to activation of system xC-, in order to increase cysteine influx and GSH synthesis; simultaneous efflux of glutamate into interstitial space may activate peripheral NMDA receptors, inducing myalgia (Rebalka et al., 2019).
In the brain, extracellular glutamate concentration is partially controlled by system xC-, making it an essential part of glutamatergic system. System xC- is vital to antioxidant defence in the brain, and its expression and activity is rapidly upregulated under oxidative stress, also in many chemoresistant cancer cell types (Lewerenz et al., 2013). System xC- activity is increased for example in MS patients (Merckx et al., 2017). Since glutamate excitotoxicity contributes to neuronal damage in many brain diseases, noninvasive assessment of system xC- activity with PET could become a valuable tool in neurology.
PET radiopharmaceuticals
Several xC- system specific PET radiopharmaceuticals have been developed, based on the structures of L-glutamate and L-cystine. These include [18F]-5-fluoro-L-aminosuberic acid ([18F]FASu) (Webster et al., 2014; Yang et al., 2017), (2S,4R)-4-[18F]fluoroglutamate ([18F]-(2S,4R)4F-GLU) (Ploessl et al., 2012; Cooper et al., 2012), N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) (Hu et al., 2014), and (2S,4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG, BAY 94-9392) (Koglin et al., 2011; Baek et al., 2012; Baek et al., 2013; Soria et al., 2014; Kavanaugh et al., 2016; Martín et al., 2016).
In contrast to [18F]FDG, these radiopharmaceuticals do not accumulate in inflammatory tissue regions.
See also:
Literature
Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, Maher P. The cystine/glutamate antiporter system xc- in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal. 2013; 18(5): 522-555. doi: 10.1089/ars.2011.4391.
Rodríguez-Campuzano AG, Ortega A. Glutamate transporters: Critical components of glutamatergic transmission. Neuropharmacology 2021; 192: 108602. doi: 10.1016/j.neuropharm.2021.108602.
Tags: Glutamate, Glutathione, Amino acid, Transporter, Oxidative stress
Updated at: 2023-02-16
Created at: 2015-08-27
Written by: Vesa Oikonen