Methionine (Met) is a naturally occurring essential amino acid in humans. Methione 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-adenosylhomocusteine may be converted to homocysteine. Homocysteine can be used to regenerate methionine or cysteine, the only other sulfur-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., 1991).
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, especially in head and neck cancer, and inflammation, since L-methionine accumulates also in tissues with active inflammation and during tissue repair. 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.
Syrota et al (1979 and 1981) and Takasu et al. (2001) proposed using L-[methyl-11C]methionine for measurement of exocrine pancreatic function.
Arentson-Lantz EJ, Saeed IH, Frassetto LA, Masharani U, Harnish RJ, Seo Y, VanBrocklin HF, Hawkins RA, Mari-Aparici C, Pampaloni MH, Slater J, Paddon-Jones D, Lang TF. 11C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring 13C6]phenylalanine infusion with serial muscle biopsy. Ann Nucl Med. 2017; 31: 295-303.
Deloar HM, Fujiwara T, Nakamura T, Itoh M, Imai D, Miyake M, Watanuki S. Estimation of internal absorbed dose of L-[methyl-11C]methionine using whole-body positron emission tomography. Eur J Nucl Med. 1998; 25(6): 629-633.
Fischman AJ, Yu YM, Livni E, Babich JW, Young VR, Alpert NM, Tompkins RG. Muscle protein synthesis by positron-emission tomography with L-[methyl-11C]methionine in adult humans. Proc Natl Acad Sci USA 1998; 95: 12793-12798.
Harris SM, Davis JC, Snyder SE, Butch ER, Vāvere AL, Kocak M, Shulkin BL. Evaluation of the biodistribution of 11C-methionine in children and young adults. J Nucl Med. 2013; 54: 1902-1908.
Hatazawa J, Ishiwata K, Itoh M, Kameyama M, Kubota K, Ido T, Matsuzawa T, Yoshimoto T, Watanuki S, Seo S. Quantitative evaluation of L-[methyl-11C]methionine uptake in tumor using positron emission tomography. J Nucl Med. 1989: 30: 1809-1813.
Horsager J, Lausten SB, Bender D, Munk OL, Keiding S. Hepatic metabolism of 11C-methionine and secretion of 11C-protein measured by PET in pigs. Am J Nucl Med Mol Imaging 2017; 7(4): 167-173.
Huovinen R, Leskinen-Kallio S, Någren K, Lehikoinen P, Ruotsalainen U, Teräs M. Carbon-11-methionine and PET in evaluation of treatment response of breast cancer. Br J Cancer 1993; 67: 787-791.
Ishiwata K, Vaalburg W, Elsinga PH, Paans AMJ, Woldring MG. Comparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET. J Nucl Med. 1988; 29: 1419-1427.
Kuang Y, Wang F, Corn DJ, Tian H, Lee Z. Metabolism of radiolabeled methionine in hepatocellular carcinoma. Mol Imaging Biol. 2014; 16(1): 44-52.
Kubota K, Matsuzawa T, Ito M, Ito K, Fujiwara T, Abe Y, Yoshioka S, Fukuda H, Hatazawa J, Iwata R, Watanuki S, Ido T. Lung tumor imaging by positron emission tomography using C-11 L-methionine. J Nucl Med. 1985; 26: 37-42.
Lapela M, Leskinen-Kallio S, Varpula M, Grenman S, Alanen K, Någren K, Lehikoinen P, Ruotsalainen U, Teräs M, Joensuu H. Imaging of uterine carcinoma by carbon-11-methionine and PET. J Nucl Med. 1994; 35: 1618-1623.
Lapela M, Leskinen-Kallio S, Varpula M, Grénman S, Salmi T, Alanen K, Någren K, Lehikoinen P, Ruotsalainen U, Teräs M, Joensuu H. Metabolic imaging of ovarian tumors with carbon-11-methionine: a PET study. J Nucl Med. 1995; 36: 2196-2200.
Leskinen S, Pulkki K, Knuuti J, Kirvelä O, Lehikoinen P, Någren K, Ruotsalainen U, Teräs M, Wegelius U, Salminen E. Transport of carbon-11-methionine is enhanced by insulin. J Nucl Med. 1997; 38: 1967-1970.
Leskinen-Kallio S, Någren K, Lehikoinen P, Ruotsalainen U, Joensuu H. Uptake of 11C-methionine in breast cancer studied by PET. Br J Cancer 1991a; 64: 1121-1124.
Leskinen-Kallio S, Ruotsalainen U, Någren K, Teräs M, Joensuu H. Uptake of carbon-11-methionine and fluorodeoxyglucose in non-Hodgkin’s lymphoma: a PET study. J Nucl Med. 1991b; 32: 1211-1218.
Leskinen-Kallio S, Någren K, Lehikoinen P, Ruotsalainen U, Teräs M, Joensuu H. Carbon-11-methionine and PET is an effective method to image head and neck cancer. J Nucl Med. 1992; 33: 691-695.
Lindholm P, Leskinen-Kallio S, Minn H, Bergman J, Haaparanta M, Lehikoinen P, Någren K, Ruotsalainen U, Teräs M, Joensuu H. Comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methione in head and neck cancer. J Nucl Med. 1993; 34: 1711-1716.
Lindholm P, Leskinen S, Någren K, Lehikoinen P, Ruotsalainen U, Teräs M, Joensuu H. Carbon-11-methionine PET imaging of malignant melanoma. J Nucl Med. 1995; 36: 1806-1810.
Lundqvist H, Stalnacke CG, Langstrom B, Jones B. Labeled metabolites in plasma after intravenous administration of [11CH3]-L-methionine. In Greitz T et al. (eds.) The metabolism of the human brain studied with positron emission tomography. New York, Raven Press, 1985: 233-240.
Morooka M, Kubota K, Kadowaki H, Ito K, Okazaki O, Kashida M, Mitsumoto T, Iwata R, Ohtomo K, Hiroe M. 11C-Methionine PET of acute myocardial infarction. J Nucl Med. 2009; 50: 1283-1287.
Nuutinen J, Leskinen S, Lindholm P, Söderström K-O, Någren K, Huhtala S, Minn H. Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas. Eur J Nucl Med. 1998; 25: 729-735.
Nuutinen J, Jyrkkiö S, Lehikoinen P, Lindholm P, Minn H. Evaluation of early response to radiotherapy in head and neck cancer measured with [11C]methionine-positron emission tomography. Radiother Oncol. 1999; 52: 225-232.
Nuutinen J, Sonninen P, Lehikoinen P, Sutinen E, Valavaara R, Eronen E, Norrgård S, Kulmala J, Teräs M, Minn H. Radiotherapy treatment planning and long-term follow-up with [11C]methionine PET in patients with low-grade astrocytoma. Int J Radiation Oncology Biol Phys. 2000; 48(1): 43-52.
Phelps ME, Barrio JR, Huang SC, Keen RE, Chugani H, Mazziotta JC. Criteria for the tracer kinetic measurement of cerebral protein synthesis in humans with positron emission tomography. Ann Neurol. 1984; 15: S192-S202.
Stern PH, Wallace CD, Hoffman RM. Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol. 1984; 119(1): 29-34.
Syrota A, Comar D, Cerf M, Plummer D, Mazière M, Kellershohn C. [11C]Methionine pancreatic scanning with positron emission computed tomography. J Nucl Med. 1979; 20: 778-781.
Syrota A, Dop-Ngassa M, Cerf M, Paraf A. 11C-L-methionine for evaluation of pancreatic exocrine function. Gut 1981; 22: 907-915.
Syrota A, Collard P, Paraf A. Comparison of 11C-L-methionine uptake by the parotid gland and pancreas in chronic pancreatitis studied by positron emission tomography. Gut 1983; 24: 637-641.
Takasu A, Shimosegawa T, Shimosegawa E, Hatazawa J, Nagasaki Y, Kimura K, Fujita M, Toyota T. [11C]Methionine positron emission tomography for the evaluation of pancreatic exocrine function in chronic pancreatitis. Pancreas 2001; 22(2): 203-209.
Thackeray JT, Bankstahl JP, Wang Y, Wollert KC, Bengel FM. Targeting amino acid metabolism for molecular imaging of inflammation early after myocardial infarction. Theranostics 2016; 6(11): 1768-1779.
Utriainen M, Metsähonkala L, Salmi TT, Utriainen T, Kalimo H, Pihko H, Mäkipernaa A, Harila-Saari A, Jyrkkiö S, Laine J, Någren K, Minn H. Metabolic characterization of childhood brain tumors - comparison of 18F-fluorodeoxyglucose and 11C-methionine positron emission tomography. Cancer 2002; 95: 1376-1386.
Created at: 2017-06-27
Updated at: 2018-05-14
Written by: Vesa Oikonen