@misc{oai:repo.qst.go.jp:00061840,
 author = {Toyohara, Jun and Kumata, Katsushi and Nakao, Ryuji and Kikuchi, Tatsuya and Fukushi, Kiyoshi and Suzuki, Kazutoshi and Irie, Toshiaki and 豊原 潤 and 熊田 勝志 and 中尾 隆士 and 菊池 達矢 and 福士 清 and 鈴木 和年 and 入江 俊章},
 month = {Oct},
 note = {Purpose: In order to obtain a thymidine analog that might prove simpler to use for imaging DNA synthesis and stimulate more widespread use of such agents, we evaluated 5-[14C]methyl-4'-thio-2'-deoxyuridine ([14C]4'-thiothymidine) as a potential 11C-labeled proliferation marker. Methods: 5-Methyl-4'-thio-2'-deoxyuridine and labeling precursor 5-trimethylstannyl-4'-thio-2'-deoxyuridine were synthesized by adapting procedure described previously [1-2]. The rapid methylation of 5-trimethylstannyl-4'-thio-2'-deoxyuridine via a palladium mediated Stille-coupling reaction with [14C]methyl iodide was performed by adapting previously described procedure [3]. Resultant [14C]4'-thiothymidine was purified by the semi-preparative HPLC. A steady-state accumulation rate, Ki (ml medium/min/g cells), was calculated from the slope of the accumulation versus time plot of in vitro C6 glioma tracer uptake. The in vivo potential of [14C]4'-thiothymidine was evaluated by distribution study of EMT-6 mammary carcinoma-bearing mice. Gemcitabine, a potent inhibitor of DNA synthesis, was used to modulate cell proliferation [4]. Results: All the compounds were characterized by 1H NMR spectroscopy and mass spectrometry. The [14C]4'-thiothymidine was obtained in 31-41% radiochemical yield (calculated from [14C]methyl iodide) at 130oC, 5 min reaction in DMF. The radiochemical purity of [14C]4'-thiothymidine was >99% and the specific activity was 2.04 GBq/mmol (according to the specific activity of [14C]methyl iodide). The accumulation of [14C]4'-thiothymidine was linear over 60 min in C6 glioma, and net accumulation rate, Ki, was calculated as 0.21. In vivo distribution study showed that cumulative accumulation of radioactivity in proliferating tissues (spleen, thymus, duodenum and tumor). On the other hand, radioactivity of non-proliferating tissues (lung, liver, kidney and muscle) was rapidly cleared in parallel with the clearance of blood radioactivity. The tumor uptake of [14C]4'-thiothymidine was high (8.8 1.2%ID/g at 60 min) and selective (Tumor to blood ratio: 12.2 5.9 at 60 min). Gemicitabine pretreatment significantly reduced the tumor uptake of [14C]4'-thiothymidine (Control:10.0 1.3 %ID/g; 0.5 mg/kg 30 min: 6.1 1.4%ID/g; 40 mg/kg 3 h: 3.2 1.5%ID/g). Conclusion: The labeling procedure was rapid and found to be suitable for 11C-labeling. Positron-labeled 5-methyl-4'-thio-2'-deoxyuridine should be useful for imaging DNA synthesis by PET. References: [1] Secrist JA III et al. J Med Chem 34:2361-66, 1991; [2] Toyohara J et al. J Nucl Med 43:1218-26, 2002; [3] Samuelsson1 L, Långström B. J Label Compd Radiopharm 46:263-72, 2003; [4] Borbath I et al. Eur J Nucl Med 29:19-27, 2002., Annual Congress of the European Association of Nuclear Medicine},
 title = {Basis of 5-[14C]methly-4'-thio-2'-deoxyuridine as a potential 11C-labeled cell proliferation marker:in vitro cell uptake and in vivo distribution in tumor-bearing mice.},
 year = {2006}
}