In-1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid-L-homoalanine

A variety of C- and F-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-[C]leucine, -[C]methyl-l-methionine ([C]MET), and l-[C]tyrosine, and of non-natural amino acids, such as [C]aminoisobutyric acid, [C]1-aminocyclopentane-1-carboxylic acid, and [C]1-aminocyclobutane-1-carboxylic acid. I-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 B (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-[C]MET, [F]fluorotyrosine, l-[C]leucine, and [F]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 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; leucine is an exception because it is quantitatively incorporated into proteins. The functions of these natural amino acid imaging agents are based on amino acid transport and protein incorporation. Lee et al. (8) synthesized a series of In-labeled alanine and lysine derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), DO3A, and DO2A. Based on their cellular accumulation in tumor cells, In-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-l-homoalanine (In-DO3A-H) was selected for use with single-photon emission computed tomography (SPECT) imaging studies in tumor-bearing nude mice.