8-[I]Iodo-L-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid

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 (3). These amino acids are composed of naturally occurring amino acids, such as l-[C]leucine, l-[C]methionine ([C]MET), and l-[C]tyrosine, and non-natural amino acids, such as [C]aminoisobutyric acid, [C]1-aminocyclopentane-1-carboxylic acid, and [C]1-aminocyclobutane-1-carboxylic acid. There are also I-labeled amino acids, such as l-phenylalanine and l-tyrosine, which are used in imaging in oncology (1, 4, 5). To date, 20 amino acid transporter systems have been identified (1). Most of the amino acids are taken up by tumor cells not only through the Na-independent L, T, and ASC transporter systems but also by the Na-dependent A and B transporter systems (6). These amino acids are retained in tumor cells because of their higher metabolic activities than most normal cells (1). Malignant transformation increases the use of amino acids for energy, protein synthesis, and cell division. Tumor cells often overexpress in the transporter systems (7). l-[C]MET, [F]fluoro- l-m-tyrosine, l-[C]leucine, and [F]fluoro-α-methyl tyrosine have been widely used in the detection of tumors (2, 6) because they are moved into cells by various amino acid transporters and are incorporated into proteins. The fraction of radiolabeled amino acid incorporated into proteins is usually small compared with the total amount taken up into the cell . Recently, it was reported that 75% of l-[C]leucine was incorporated into proteins of monkey brains at 60 min after injection of the tracer as measured by biochemical analysis and PET imaging (8). These natural amino acid imaging scans are based on amino acid transport and protein incorporation. No non-natural amino acids are incorporated into proteins (2, 9). These amino acids are rapidly transported into tumor cells. They are retained inside the tumor cells because of their high cellular metabolism and their high activity of the amino acid transporters. Recently, new l-tyrosine analogs, such as -(2-[F]fluoroethyl)-l-tyrosine ([F]FET), were synthesized and evaluated as amino acid PET tracers for the detection of brain tumors with a higher specificity as compared with [F]fluoro-2-deoxy-2-d-glucose ([F]FDG). 8-[I]Iodo- l-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid ([I]ITIC) is a cyclic analog of L-tyrosine. It accumulated moderately in human pancreatic carcinoma and glioblastoma cells but markedly in human prostate tumor cells, with only a marginal incorporation into proteins (10-13). The cellular uptake into the prostate tumor cells was not dependent on most amino acid transport systems but tentatively dependent on the membrane potential and amino acid transporter T system. [I]ITIC is being developed as a single-photon emission computed tomography (SPECT) imaging agent of human prostate cancer.