Background

[PubMed]

A variety of ¹¹C- and ¹⁸F-labeled amino acids have been studied for potential use in positron emission tomography (PET) oncology (1, 2). Most brain tumors show an increased uptake of amino acids as compared with normal brain tissues (3). These amino acids are composed of naturally occurring amino acids, such as L-[¹¹C]leucine, S-[¹¹C]methyl-L-methionine ([¹¹C]MET), and L-[¹¹C]tyrosine, and non-natural amino acids, such as [¹¹C]aminoisobutyric acid, [¹¹C]1-aminocyclopentane-1-carboxylic acid, and [¹¹C]1-aminocyclobutane-1-carboxylic acid. ¹²³I-Labeled amino acids are also used in oncological imaging (1, 4, 5).

Some 20 amino acid transporter systems have been identified (1). Most amino acids are taken up by tumor cells through an energy-independent L-type amino acid transporter system, a Na-dependent transporter system A, or a Na⁺-dependent system B⁰ (6). They are retained in tumor cells due to their metabolic activities, including incorporation into proteins, which are higher than most normal cells (1). Malignant transformation increases the use of amino acids for energy, protein synthesis, and cell division. Tumor cells have been found to have overexpressed transporter systems (7). L-[¹¹C]MET, [¹⁸F]fluorotyrosine, L-[¹¹C]leucine, and [¹⁸F]fluoro-α-methyl tyrosine have been widely used in the detection of tumors (2, 6) but are not approved by the United States Food and Drug Administration. These agents are moved into cells by various amino acid transporters and are incorporated into proteins. The fraction of radiolabeled amino acid that is incorporated into protein is usually small compared to the total amount taken up into the cell except for leucine which is quantitatively incorporated into proteins. These natural amino acid images are based on amino acid transport and protein incorporation.

[¹¹C]MET has been widely used in the detection of brain, head and neck, lung, and breast cancers as well as lymphomas (2) [PubMed]. [¹¹C]MET can cross the blood–brain barrier, and while it is incorporated mainly into proteins, but [¹¹C]MET is also incorporated into lipid, RNA, and DNA. [¹¹C]MET PET imaging is more sensitive to radiotherapy compared to [¹⁸F]FDG and is useful for monitoring treatment of cancer. S-[¹¹C]Methyl-L-cysteine ([¹¹C]MCYS), an analog of [¹¹C]MET, was evaluated as a PET tumor imaging agent (8).

Synthesis

[PubMed]

A continuous flow procedure was automated for the synthesis of [¹¹C]methyl iodide from [¹¹C]CO₂ and [¹¹C]MCYS by ¹¹C-meythylation of the desmethyl precursor L-cysteine with [¹¹C]methyl iodide (8). The preparation was completed in 12 min after the end of bombardment, with a yield of >50% based on [¹¹C]methyl iodide. The radiochemical purity of [¹¹C]MCYS was >99%, with >90% enantiomeric purity. The specific activity of [¹¹C]MCYS was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Deng et al. (8) showed that [¹¹C]MCYS accumulation in Hepa1-6 mouse hepatocellular carcinoma cells was reduced by 80% in the presence of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH, an L-type transporter inhibitor). The accumulation of [¹¹C]MCYS was not affected by the presence of Na⁺ ions. On the other hand, no inhibition was observed in the presence of N-methyl-α-aminoisobutyric acid (an A-type transporter inhibitor) and l-alanine/serine/cysteine (System ASC). Specific transport of [¹¹C]MCYS in Hepa1-6 cells was mediated mainly by System L and was independent of sodium ions.

Animal Studies

Human Studies

[PubMed]

[¹¹C]MCYS and [¹⁸F]FDG PET brain imaging scans were performed in a 45-year-old male patient with grade IV glioma (8). [¹⁸F]FDG exhibited heterogeneous radioactivity in patches, whereas [¹¹C]MCYS showed high radioactivity accumulation in the tumor lesion, which was confirmed with histopathological examination. Specific uptake was not determined.

References

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2.

Laverman P., Boerman O.C., Corstens F.H., Oyen W.J. Fluorinated amino acids for tumour imaging with positron emission tomography. Eur J Nucl Med Mol Imaging. 2002;29(5):681–90. [PubMed: 11976809]

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Herholz K., Heiss W.D. Positron emission tomography in clinical neurology. Mol Imaging Biol. 2004;6(4):239–69. [PubMed: 15262239]

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Langen K.J., Pauleit D., Coenen H.H. 3-[(123)I]Iodo-alpha-methyl-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol. 2002;29(6):625–31. [PubMed: 12234586]

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Lahoutte T., Caveliers V., Camargo S.M., Franca R., Ramadan T., Veljkovic E., Mertens J., Bossuyt A., Verrey F. SPECT and PET amino acid tracer influx via system L (h4F2hc-hLAT1) and its transstimulation. J Nucl Med. 2004;45(9):1591–6. [PubMed: 15347729]

6.

Langen K.J., Jarosch M., Muhlensiepen H., Hamacher K., Broer S., Jansen P., Zilles K., Coenen H.H. Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas. Nucl Med Biol. 2003;30(5):501–8. [PubMed: 12831987]

7.

Saier M.H., Daniels G.A., Boerner P., Lin J. Neutral amino acid transport systems in animal cells: potential targets of oncogene action and regulators of cellular growth. J Membr Biol. 1988;104(1):1–20. [PubMed: 3054116]

8.

Deng H., Tang X., Wang H., Tang G., Wen F., Shi X., Yi C., Wu K., Meng Q. S-11C-methyl-L-cysteine: a new amino acid PET tracer for cancer imaging. J Nucl Med. 2011;52(2):287–93. [PubMed: 21233188]