Evaluation of 4'-[methyl-14C]thiothymidine for in vivo DNA synthesis imaging.
Evaluation of 4'-[methyl-14C]thiothymidine for in vivo DNA synthesis imaging.
复制标题
评估 4-[甲基-14C]硫胸苷在体内 DNA 合成成像中的应用。
DOI：
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发表时间：
2006
影响因子：
9.3
通讯作者：
Kazutoshi Suzuki
中科院分区：
文献类型：
--
作者：
J. Toyohara;K. Kumata;K. Fukushi;T. Irie;Kazutoshi Suzuki
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我们评估了 4'-[methyl-11C]thiothymidine ([methyl-11C]S-dThd)，以获得胸苷类似物，该类似物可能更容易用于 DNA 合成成像，并且可能遵循与其替代物相同的生物化学。
方法
[Mmethyl-14C]S-dThd 是通过 5-三甲基甲锡烷基-4'-硫代-2'-脱氧尿苷通过钯介导的 Stille 与 14C-碘甲烷偶联反应快速甲基化合成的。通过高效液相色谱 (HPLC) 分析在人血液中孵育时 [methyl-14C]S-dThd 的降解情况。通过研究 [methyl-14C]S-dThd 在 EMT-6 乳腺癌小鼠中的分布，评估了 [methyl-14C]S-dThd 的体内潜力。 2-Fluoro-2'-deoxycytidine 是一种有效的 DNA 合成抑制剂，用于调节细胞增殖。还进行了组织提取以研究 [methyl-14C]S-dThd 掺入 DNA 的情况。
结果
在 130 摄氏度下，在 N,N-二甲基甲酰胺中反应 5 分钟，然后进行半制备型 HPLC 纯化，以 31%-41% 的放射化学产率（根据 14C-碘甲烷计算）获得[甲基-14C]S-dThd。 [methyl-14C]S-dThd的放射化学纯度>99%，比活度为2.04 GBq/mmol（根据14C-碘甲烷比活度）。 [2-14C]胸苷与人血一起孵育时会快速降解。相比之下，[methyl-14C]S-dThd 很稳定，60 分钟时降解率 <3%。体内分布研究显示放射性在增殖组织（脾、胸腺、十二指肠和肿瘤）中积累。另一方面，非增殖组织（肺、肝、肾和肌肉）的放射性与血液放射性的清除同时迅速被清除。肿瘤对[甲基-14C]S-dThd 的摄取较高（60 分钟时每克注射剂量为 8.8%）且具有选择性（肿瘤与血液的比率，60 分钟时为 12.2）。 2-Fluoro-2'-deoxycytidine 预处理显着减少肿瘤对 [methyl-14C]S-dThd 的摄取。通过 4-[N-甲基-14C]碘安替比林的摄取测量的相对血流量在治疗组和未治疗组之间相似。组织提取研究表明，注射 [methyl-14C]S-dThd 后 60 分钟，快速增殖组织的大部分总组织放射性在 DNA 级分中恢复。
结论
标记过程快速，适合 11C 标记。正电子标记的 4'-硫胸苷应该可用于通过 PET 对 DNA 合成进行成像。
UNLABELLED
We evaluated 4'-[methyl-11C]thiothymidine ([methyl-11C]S-dThd) to obtain a thymidine analog that might prove simpler to use for imaging DNA synthesis and that might follow the same biochemistry as its surrogate.
METHODS
[Methyl-14C]S-dThd was synthesized by rapid methylation of 5-trimethylstannyl-4'-thio-2'-deoxyuridine via a palladium-mediated Stille coupling reaction with 14C-methyl iodide. Degradation of [methyl-14C]S-dThd, when incubated in human blood, was analyzed by high-performance liquid chromatography (HPLC). The in vivo potential of [methyl-14C]S-dThd was evaluated by studying its distribution in EMT-6 mammary carcinoma-bearing mice. 2-Fluoro-2'-deoxycytidine, a potent inhibitor of DNA synthesis, was used to modulate cell proliferation. Tissue extraction was also performed to investigate the incorporation of [methyl-14C]S-dThd into DNA.
RESULTS
[Methyl-14C]S-dThd was obtained in a 31%-41% radiochemical yield (calculated from 14C-methyl iodide) at 130 degrees C, 5-min reaction in N,N-dimethylformamide followed by semipreparative HPLC purification. The radiochemical purity of [methyl-14C]S-dThd was >99% and the specific activity was 2.04 GBq/mmol (according to the specific activity of 14C-methyl iodide). [2-14C]Thymidine, when incubated with human blood, demonstrated rapid degradation. In contrast, [methyl-14C]S-dThd was stable with <3% degradation at 60 min. An in vivo distribution study showed the accumulation of radioactivity in proliferating tissues (spleen, thymus, duodenum, and tumor). On the other hand, the radioactivity of nonproliferating tissues (lung, liver, kidney, and muscle) was rapidly cleared in parallel with the clearance of blood radioactivity. The tumor uptake of [methyl-14C]S-dThd was high (8.8 percentage injected dose per gram at 60 min) and selective (tumor-to-blood ratio, 12.2 at 60 min). 2-Fluoro-2'-deoxycytidine pretreatment significantly reduced the tumor uptake of [methyl-14C]S-dThd. Relative blood flow as measured by the uptake of 4-[N-methyl-14C]iodoantipyrine was similar between the treated and untreated groups. Tissue extraction studies showed that most of the total tissue radioactivity of rapidly proliferating tissues was recovered in the DNA fraction at 60 min after [methyl-14C]S-dThd injection.
CONCLUSION
The labeling procedure is rapid and suitable for 11C labeling. Positron-labeled 4'-thiothymidine should be useful for imaging DNA synthesis by PET.
影响因子：
3.1
作者：
Grierson, JR;Shields, AF
通讯作者：
Shields, AF
影响因子：
3.1
作者：
Shields, AF;Grierson, JR;Zheng, M
通讯作者：
Zheng, M
影响因子：
7.3
作者：
SECRIST, JA;TIWARI, KN;MONTGOMERY, JA
通讯作者：
MONTGOMERY, JA