Evaluation of 4′-[Methyl-11C]Thiothymidine in a Rodent Tumor and Inflammation Model

Abstract

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. 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. (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. 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.