Utilization of labeled thymidine in DNA synthesis: Studies for PET

Carbon-111-thymidine and positron emission tomography (PET) have the potential for noninvasively measuring DNA synthesis in tumors and tissues. In order to validate this potential, one needs to construct accurate biochemical models that reflect the metabolism of thymidine, including its uptake and degradation as well as its incorporation into DNA. Our studies employed thymidine labeled in the methyl position using ¹¹C, ¹⁴C, and ³H. Studies with rapidly proliferating tissues of mice demonstrated that most of the activity, 60 min after injection of labeled thymidine, was present in DNA, with smaller amounts found in metabolites. Studies in dogs, however, reveal that more activity was present in metabolites, rather than in the DNA of tumors and spleen tissue. HPLC analysis of canine blood after the injection of thymidine revealed rapid conversion of thymidine to thymine and other metabolites. We have found significant differences in the metabolism of [³H]thymidine versus thymidine labeled with radioactive carbon. These differences, which were not found when comparing ¹⁴C and ¹¹C, indicate that [³H]thymidine is not an appropriate standard for comparison with PET studies employing [¹¹C] thymidine. To accurately interpret images of [¹¹C]thymidine as representations of DNA synthesis we are developing kinetic models that take into account the metabolism of thymidine and the contribution of degradation products to the ¹¹C images.