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Evaluation of 4'-[methyl-11C]thiothymidine in a rodent tumor and inflammation model
Jun Toyohara1, Philip H Elsinga, Kiichi Ishiwata
1Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. toyohara@pet.tmig.or.jp
Unlabelled:
4'-[methyl-(11)C]thiothymidine ((11)C-4DST) is a novel radiopharmaceutical that can be used for tumor imaging because of its rapid incorporation into DNA as a substrate for DNA synthesis. The in vivo stability of (11)C-4DST is much greater than that of natural thymidine, because of the presence of a sulfur atom in the 4'-position. Here, we evaluated the tissue kinetics and biodistribution of (11)C-4DST in a rodent tumor and acute sterile inflammation model in comparison with the previously published biodistribution data of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), (18)F-FDG, (11)C-choline, (11)C-methionine, and 2 σ-receptor ligands in the same animal model.
Methods:
C6 tumor cells were implanted subcutaneously into the right shoulder and turpentine (0.1 mL) was injected intramuscularly into the left hind leg of male Wistar rats 11 d and 24 h, respectively, before the scanning day. The animals were anesthetized with isoflurane, and (11)C-4DST (20-50 MBq) was injected intravenously. A dynamic PET scan was performed for 60 min with either the shoulder or hind leg region in the field of view. The animals were sacrificed, and a biodistribution study was performed.
Results:
(11)C-4DST showed the highest tumor uptake (standardized uptake value, 4.93) of all radiopharmaceuticals tested. Its tumor-to-muscle concentration ratio (12.7) was similar to that of (18)F-FDG (13.2). The selectivity of (11)C-4DST for tumor as compared with acute inflammation was high (37.7), comparable to that of the σ-ligand (18)F-FE-SA5845 and much higher than that of (18)F-FDG (3.5). Rapidly proliferating tissues (tumor and bone marrow) showed a steadily increasing uptake. In inflamed muscle, (11)C-4DST showed relatively rapid washout, and tracer concentrations in inflamed and noninflamed muscle were not significantly different at intervals greater than 40 min. Competition of endogenous thymidine for (11)C-4DST uptake in target tissues was negligible, in contrast to competition for (18)F-FLT uptake. Thus, pretreatment of animals with thymidine phosphorylase was not required before PET with (11)C-4DST.
Conclusion:
In our rodent model, (11)C-4DST showed high tumor uptake (sensitivity) and high tumor selectivity. The different kinetics of (11)C-4DST in rapidly proliferating and inflammatory tissue may allow distinction between tumor and acute inflammation in a clinical setting. These promising results for (11)C-4DST warrant further investigation in PET studies in patients with various types of tumors.
