Feasibility studies of 4′-[methyl-¹¹C]thiothymidine as a tumor proliferation imaging agent in mice☆

Abstract 

This study reports on the radiosynthesis and feasibility studies of 4′-[methyl-¹¹C]thiothymidine ([methyl-¹¹C]S-dThd) as a tumor proliferation imaging agent. [Methyl-¹¹C]S-dThd was synthesized by rapid methylation of corresponding 5-trimethylstannyl- or 5-tributylstannyl-precursor via a palladium-promoted Stille cross-coupling reaction with [¹¹C]methyl iodide. The decay-corrected radiochemical yields of [methyl-¹¹C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor based on [¹¹C]CO₂ were 18.9% and 14.5%, respectively. The radiochemical purity of [methyl-¹¹C]S-dThd was always greater than 99%. The specific activities of [methyl-¹¹C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor were 47 GBq/μmol and 121 GBq/μmol, respectively, at the end of the synthesis. The total synthesis time was 30 min after the end of bombardment. The comparison between in vivo distribution of [methyl-¹⁴C]S-dThd and that of [methyl-³H]FLT showed that tracer uptake was comparable in nonproliferating tissues. In contrast, [methyl-¹⁴C]S-dThd showed significantly higher uptake in proliferating tissues than did [methyl-³H]FLT. [Methyl-¹¹C]S-dThd uptake levels in five different tumor tissues were well correlated with the DNA synthesis levels determined by [2-¹⁴C]thymidine DNA incorporation. At 30 min after injection, plasma analysis found 95% of the activity in unmetabolized form. The microPET imaging of the C6 glioma xenograft showed significantly high uptake in the tumor and urinary bladder, followed by the intestine and marrow. Our results demonstrated that the tumor uptake of [methyl-¹¹C]S-dThd was higher than that of [methyl-³H]FLT and was well correlated with the DNA synthesis level. Consequently, 4′-[methyl-¹¹C]thiothymidine has promise for the imaging of tumor cell proliferation by positron emission tomography.

Keywords: ¹¹C, DNA synthesis, S-dThd, Proliferation, Tumor, PET