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Methyl- (11)C -4 -thiothymidine Chopra AMolecular Imaging and Contrast Agent Database (MICAD)-/-ä 2004[]; ä (ä): äMost anti-cancer drugs are aimed at curbing the processes of rapid cell proliferation and an increased rate of DNA synthesis, which are both necessary for the progression of all cancers and the development of neoplastic tumors. Usually invasive procedures such as biopsies are used to confirm the presence of malignant tumors, but it can be difficult to take multiple biopsies from a patient if the cancer has metastasized to several different areas of the body (1). Therefore, non-invasive imaging methods that use radiolabeled thymidine analogs (a nucleoside present only in the DNA) in conjunction with positron emission tomography (PET) have been developed to detect tumors and to evaluate the efficacy of anti-cancer treatments in animals and humans (1). Initially, (11)C-labeled thymidine was developed to visualize cancerous tumors, but this radiolabeled compound is quickly metabolized in the cell and has been determined to have limited application in the clinic (2). Subsequently, (18)F-labeled PET agents with a thymidine base, such as 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]-FLT) and 1-(2'-deoxy-2'-[(18)F]fluoro-beta-D-arabinofuranosyl) thymine ([(18)F]-FMAU), were generated and evaluated for the visualization of neoplastic tumors. Among these, FLT is phosphorylated by thymidine kinase 1 (a cytosolic isozyme of thymidine kinase), but the phosphorylated molecule is not incorporated into the cellular DNA and is trapped within the cell (2). Hence, [(18)F]-FLT is considered to be a surrogate marker for the visualization of cell proliferation under in vivo conditions. In addition, this cell proliferation tracer has several limitations that have been discussed elsewhere (3). The second tracer, [(18)F]-FMAU, has to be phosphorylated by thymidine kinase 2 (TK2), a mitochondrial enzyme, before it is incorporated into the DNA (2). However, [(18)F]-FMAU is considered suitable only for the detection of neoplasia in the pelvic region or for visualization of tumors that have metastasized to the bone, because with this radiolabeled compound there is a high retention of label in the liver, kidneys, and the myocardium (2). It has also been reported that there is no correlation between the uptake of a TK2-selective arabinothymidine substrate and the proliferation of cells in a malignant tumor (3). With the information described above, in an effort to produce an alternative tracer that can be used to visualize tumor proliferation, Toyohara et al. synthesized 4'-thiothymidine (in this molecule, the 4'-oxo of thymidine is substituted with a 4'-sulfur) and showed that its methylated and (14)C-labeled derivative, 4'-methyl-[(14)C]-thiothymidine ([(14)C]-4DST), accumulated mainly in rapidly proliferating tissues in mice (spleen, duodenum, and thymus), including the xenograft tumors (4). It has also been shown that the label from [(14)C]-4DST is present mainly in the DNA fraction of these tissues. On the basis of these observations, (11)C-labeled 4'-methyl-thiothymidine ([(11)C]-4DST) was synthesized and evaluated for the visualization of cell proliferation with PET in mice bearing xenograft tumors generated from several different cell lines (3). The biodistribution and use of [(11)C]-4DST for the imaging of brain tumors in humans with PET was investigated in a recent pilot study (5).ä |
