[F]Fluoromethyl-d-tyrosine

Cancerous tumors are formed by characteristically high levels of proliferating cells that have a constant high requirement for basic building blocks such as carbohydrates, nucleotides, and amino acids (AA) to maintain a suitable metabolic rate and to continue the synthesis of macromolecules such as DNA and proteins to sustain their phenotype (1). Because of the high carbohydrate demand of tumor cells, (F)fluorodeoxy-glucose ((F)FDG), which is not metabolized by the cells and as a consequence accumulates in neoplastic tumors, was developed to screen for cancers using positron emission tomography (PET) imaging. Although shown to be suitable for the detection of certain cancers (2), the main limitation of using (F)FDG to detect tumors is that it tends to accumulate in some normal tissues (e.g., brain and heart) and inflamed tissues (3-5). Therefore, several C- and F-labeled AAs and their analogs, including l- and d-methyl-C-methionine (l- and d-(C)MET) and l- and d--(F)fluoromethyl-tyrosine (l- and d-(F)FMT), were developed as an alternative and have been evaluated for the uptake by and PET imaging of normal and tumor tissues (6, 7). Radiolabeled l-isomers of AAs behave like the naturally occurring compounds in a biological system, can be used for protein synthesis, are easily metabolized by mammalian cells, and have been shown to accumulate in non-target tissue in addition to tumors (8). In contrast, the d-isomers are unnatural and, compared with the l-isomers, C-labeled d-amino acids have been shown to have a higher tumor accumulation (9-12). Although different AA transport systems are involved in the uptake of AAs, the AAs are transported primarily by the l AA transport systems (designated as LAT1 and LAT2), which are not sodium-dependent and can transport both the l- and d-isomers (7, 13), including those containing a branched chain or an aromatic moiety (14). Also, the LAT1 was reported to be expressed in the brain, spleen, placenta, and the testis (15) and was reported to be overexpressed in malignant tumors (16, 17). Tsukada et al. reported the tumor/blood uptake of the d-isomers of (F)FMT, (F)fluoroethyl-tyrosine, and (F)fluoropropyl-tyrosine in tumor-bearing mice was 181%, 137%, and 101%, respectively, compared with their l homologs, indicating that the d-isomers could be potential PET imaging agents (13). In another study, d-(F)FMT was suggested to be a better PET tracer than the l- and d-isomers of (C)MET because it showed lower accumulation in various normal organs and, compared with (F)FDG, did not accumulate in inflamed tissue (7). Urakami et al. studied the uptake of l- and d-(F)FMT in cultured cells under conditions and evaluated the use of these radiolabeled compounds for the imaging of abdominal and brain tumors in rats and mice, respectively (18).