(S)-2-Amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid

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.