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 compared with uptake in normal brain tissue (3). These amino acids are composed of naturally occurring amino acids, such as l-[¹¹C]leucine, l-[¹¹C]methionine, 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 for imaging in oncology, although no radiolabeled amino acid is approved in the US at present (1, 4, 5).

More than twenty amino acid transporter systems have been identified (1). Most of the amino acids are taken up by tumor cells through an energy-independent l-type amino acid transporter system and the Na-dependent transporter system A, as well as through the Na⁺-dependent system B⁰ (6). The amino acids are retained in tumor cells, including incorporation into proteins, due to their high metabolic activities, which are higher than metabolic activities of most normal cells (1). Malignant transformation increases the use of amino acids for energy, protein synthesis, and cell division. Tumor cells were 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 they are not approved by the United States Food and Drug Administration. These radiolabels are moved into cells by various amino acid transporters and are incorporated into proteins, although only l-leucine is quantitatively incorporated into proteins. The fraction of radiolabeled amino acids that is incorporated into proteins is usually small compared to the total amount taken up into the cell. Imaging techniques that use natural amino acids are based on amino acid transport and protein incorporation.

Non-natural amino acids are not incorporated into proteins (2, 8); instead, they are rapidly transported into tumor cells. They are retained inside the tumor cells because of their high cellular metabolism and the high activity of the amino acid transporters. A new l-tyrosine analog, O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET), has been synthesized and evaluated as an amino acid PET tracer for the detection of brain tumors. [¹⁸F]FET has a higher specificity than [¹⁸F]FDG (8). (S)-2-Amino-3-[1-(2-[¹⁸F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid ((S)-[¹⁸F]4) has been found to be a substrate for the cationic amino acid transporter, which transports the naturally occurring amino acids (l-histidine, l-arginine, and l-lysine) (9). (S)-[¹⁸F]4 was synthesized with Click reaction and evaluated as an amino acid PET tracer for the detection of brain tumors.

Synthesis

[PubMed]

McConathy et al. (9) reported the synthesis of (S)-[¹⁸F]4 in a multi-step reaction. 2-[¹⁸F]Fluoroethyl azide was prepared using the tosylate (S)-precursor in the presence of K[¹⁸F]F/K2.2.2/K₂CO₃ (85°C, 15 min). Cycloaddition reaction of 2-[¹⁸F]fluoroethyl azide to the alkyne precursor was carried out in N,N-dimethylformamide for 15 min at room temperature. The purified reaction product was subjected to acid hydrolysis to form (S)-[¹⁸F]4. (R)-[¹⁸F]4 was prepared similarly using the tosylate (R)-precursor. (S)-[¹⁸F]4 and (R)-[¹⁸F]4 were obtained with radiochemical yields of 51 ± 8% (n = 5) and 57 ± 6% (n = 3), respectively. The radiochemical purity was >98% with a total synthesis time of ~150 min. The specific activities for (S)-[¹⁸F]4 and (R)-[¹⁸F]4 were 37 and 11 GBq/µmol (1 and 0.3 Ci/µmol) at the time of biological studies, respectively.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

McConathy et al. (9) showed that (S)-[¹⁸F]4 accumulation in 9L rat gliosarcoma cells was reduced by 50%, 18%, and 89% in the presence of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH, an L-type transporter inhibitor), N-methyl-α-aminoisobutyric acid (an A-type transporter inhibitor), and l-alanine/serine/cysteine (ASC, control), respectively. The further inhibition of uptake by BCH under sodium-free conditions suggests (S)-[¹⁸F]4 is a substrate for system L transport. (S)-[¹⁸F]4 accumulation in cells was inhibited by 50% with l-Arg and by 69% with l-His, suggesting involvement of cationic amino acid transport. In contrast, (R)-[¹⁸F]4 accumulation was not mediated by system L or by cationic amino acid transport. (R)-[¹⁸F]4 accumulation was only partially inhibited (36%) by ASC.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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McConathy J., Zhou D., Shockley S.E., Jones L.A., Griffin E.A., Lee H., Adams S.J., Mach R.H. Click synthesis and biologic evaluation of (R)- and (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid for brain tumor imaging with positron emission tomography. Mol Imaging. 2010;9(6):329–42. [PubMed: 21084029]