Methionine (Met) is a naturally occurring essential amino acid in humans. Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, and phospholipids. It is used in protein synthesis, and as S-adenosyl-L-methionine in enzymatic transmethylation reactions. When S-adenosylmethione has lost its methyl group, the resulting S-adenosylhomocysteine may be converted to homocysteine. Homocysteine can be used to regenerate methionine or cysteine, the only other sulphur-containing amino acid.
L-Methionine is transported into cells via the L-type amino acid transporter 1 (LAT1). In tumours, the demand for L-methionine increases, with increased protein and phospholipid synthesis (Stern et al., 1984; Leskinen-Kallio et al., 1991a).
L-Methionine can be labelled with the positron emitting radionuclide 11C to obtain the chemically identical PET tracer. 11C has been attached to the methyl and carboxylic group, producing L-[methyl-11C]methionine and L-[1-11C]methionine, respectively. When L-methionine is labelled to the methyl group, the radionuclide will follow the methyl group in transmethylation reactions into various small and large molecules. Transmethylation reactions of carboxylic-labelled L-methionine leads to formation of S-adenosyl-L-[1-11C]methionine, and further to S-adenosyl-L-[1-11C]homocysteine, which is again precursor of protein and methionine synthesis (Ishiwata et al., 1988). Decarboxylation reactions lead to formation of [11C]CO2, which, in addition to pulmonary clearance, can be incorporated into nonvolatile compounds such as [11C]urea, [11C]glucose, and [11C]lactate. In tumours, the total uptake rates of the two L-methionines are similar, but in healthy tissues, especially in the liver the uptake kinetics and the labelled compounds are different (Ishiwata et al., 1988).
L-[11C]methionine tracers are mainly used to detect malignant tumours, for instance head and neck cancer (Leskinen-Kallio et al., 1992a and 1994; Lindholm et al., 1993 and 1995), breast cancer (Leskinen-Kallio et al., 1991a; Huovinen et al., 1993), uterine carcinoma (Lapela et al., 1994), and ovarian cancer (Lapela et al., 1995). L-[11C]methionine can also detect inflammation, because L-methionine may accumulate in tissues with active inflammation and during tissue repair. Locally broken blood-brain barrier, increased perfusion, and inflammatory cells may lead to increased L-[11C]methionine uptake in brain infarction, haematoma, radiation necrosis, and infection (Nakajima et al., 2017). When both [18F]FDG and [11C]methionine PET are performed, then accumulation of both in a lesion indicates high-grade malignancy; accumulation of only methionine indicates low-grade malignancy; and accumulation of only FDG indicates inflammation or granuloma (Kubota et al., 2023). The high L-[11C]methionine uptake in salivary glands and nasal epithelium may hamper the tumour imaging, but that is a common problem with tracers that target increasing metabolism. S-[11C]-methyl-L-cysteine does not accumulate in the salivary glands, but its uptake in healthy brain is higher than that of L-[11C]methionine (Parente et al., 2018).
In clinical use, the L-[methyl-11C]methionine PET data is usually analyzed using simple SUV or SUV ratio methods. Horsager et al. (2017) analyzed pig liver L-[methyl-11C]methionine data using extended Patlak plot, including kloss to account for the loss of 11C-proteins and 11C-metabolites from the liver. The flux (metabolic rate) of methionine from plasma to liver was calculated by multiplying Ki by plasma L-methionine concentration. About 17 min p.i. the plasma 11C-protein concentration increased linearly, and the slope was reported as the appearance rate of 11C-proteins in plasma, Rprot.
L-[methyl-11C]methionine can be used to measure protein synthesis in skeletal muscle (Hsu et al., 1996; Fischman et al., 1998). The assessment requires the assumption of insignificant transamination and transmethylation of amino acids that are not used in protein synthesis, which was validated by Carter et al (1999).
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Updated at: 2023-09-22
Created at: 2017-06-27
Written by: Vesa Oikonen