Pyrimidine nucleosides in molecular PET imaging of tumor proliferation

Human thymidine kinase (TK1) is a key enzyme that is up-regulated in cancer cells and phosphorylates thymidine and some of its analogs to their monophosphates. The monophosphates are converted to their di- and triphosphates by the nucleoside kinases, and some of these nucleoside triphosphates are incorporated into DNA by DNA polymerase. The nucleoside analogs are transported into cells by concentrative nucleoside transporter or equilibrative nucleoside transporter. Given the unique property of TK1 and the nucleoside transporter systems, thymidine and its analogs have been radiolabeled for positron emission tomography (PET) imaging of tumor proliferation and DNA synthesis. Because thymidine is catabolized in vivo by thymidine phosphorylase, radiolabeled thymidine has not been successful in PET imaging of tumor proliferation. However, some of its analogs have been radiolabeled and successfully used in PET imaging of cell proliferation as well as DNA synthesis. Much work has been done in synthesis, radiosynthesis, and biological evaluation of these analogs for PET imaging of tumor proliferation. We review the chemistry, radiochemistry, and biological studies published to date, including structure activity relationship and PET imaging of the radiolabeled thymidine analogs. Information on radiolabeling and PET imaging with various nucleoside analogs is presented.