title: Feasibility studies of 4'-[methyl-(11)C]thiothymidine as a tumor proliferation imaging agent in mice.
abstract: This study reports on the radiosynthesis and feasibility studies of 4'-[methyl-(11)C]thiothymidine ([methyl-(11)C]S-dThd) as a tumor proliferation imaging agent. [Methyl-(11)C]S-dThd was synthesized by rapid methylation of corresponding 5-trimethylstannyl- or 5-tributylstannyl-precursor via a palladium-promoted Stille cross-coupling reaction with [(11)C]methyl iodide. The decay-corrected radiochemical yields of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor based on [(11)C]CO(2) were 18.9% and 14.5%, respectively. The radiochemical purity of [methyl-(11)C]S-dThd was always greater than 99%. The specific activities of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor were 47 GBq/mumol and 121 GBq/mumol, 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-(14)C]S-dThd and that of [methyl-(3)H]FLT showed that tracer uptake was comparable in nonproliferating tissues. In contrast, [methyl-(14)C]S-dThd showed significantly higher uptake in proliferating tissues than did [methyl-(3)H]FLT. [Methyl-(11)C]S-dThd uptake levels in five different tumor tissues were well correlated with the DNA synthesis levels determined by [2-(14)C]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-(11)C]S-dThd was higher than that of [methyl-(3)H]FLT and was well correlated with the DNA synthesis level. Consequently, 4'-[methyl-(11)C]thiothymidine has promise for the imaging of tumor cell proliferation by positron emission tomography.
authors.affiliation: Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan. toyohara@faculty.chiba-u.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Maki
authors.initials: M
authors.lastname: Okada
authors.forename: Chie
authors.initials: C
authors.lastname: Toramatsu
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Irie
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000473:pathology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism; D013872:Thionucleosides / Q000138:chemical synthesis / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D013872:Thionucleosides; C070456:4'-thiothymidine; D004247:DNA; D013936:Thymidine