[11C]Sorafenib: Radiosynthesis and preclinical evaluation in tumor-bearing mice of a new TKI-PET tracer
[11C]Sorafenib: Radiosynthesis and preclinical evaluation in tumor-bearing mice of a new TKI-PET tracer
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DOI：
10.1016/j.nucmedbio.2013.02.002
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发表时间：
2013-05-01
影响因子：
3.1
通讯作者：
Windhorst, Albert D.
中科院分区：
文献类型：
--
作者：
Poot, Alex J.;van der Wildt, Berend;Windhorst, Albert D.
简介：酪氨酸激酶抑制剂（TKI）如索拉非尼是重要的抗癌治疗剂，迄今为止在癌症患者中具有有限的治疗响应率。如果有合适的PET示踪剂，正电子发射断层扫描（PET）可以提供选择可能从TKI治疗中获益的患者的方法。本研究的目的是用碳-11放射性标记索拉非尼（1），并评估其作为体内TKI-PET示踪剂的潜力。方法：开发了合成方法，其中索拉非尼在两个不同的位置被标记，然后在大鼠中进行代谢物分析和在荷瘤小鼠中进行PET成像研究。合成了[甲基-C-11]-1和[脲-C-11]-1，产率分别为59%和53%，纯度> 99%。通过在HPLC上与参比索拉非尼共进样确认产物的鉴别。在体内代谢物分析中，[C-11]索拉非尼被证明是稳定的。45 min后血浆中完整产物的百分比分别为90%（[甲基-C-11]-1）和96%（[尿素-C-11]-1）。由于更可靠的合成，在携带FaDu（头颈癌）、MDA-MB-231（乳腺癌）或RXF 393（肾癌）异种移植物的裸鼠中用[甲基-C-11]-1进行关于PET成像的进一步研究。在RXF 393，广泛表达索拉非尼靶抗原Raf-1的异种移植系，通过免疫组化assessedbyimmunohistochemistry.Conclusion：总之，我们合成了[C-11]索拉非尼作为PET示踪剂，它在体内是稳定的，并有能力作为PET示踪剂用于荷瘤小鼠的成像。(C)2013 Elsevier Inc. All rights reserved.
Introduction: Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo.Methods: Synthetic methods were developed in which sorafenib was labeled at two different positions, followed by a metabolite analysis in rats and a PET imaging study in tumor-bearing mice.Results: [methyl-C-11]-1 and [urea-C-11]-1 were synthesized in yields of 59% and 53%, respectively, with a purity of >99%. The identity of the products was confirmed by coinjection on HPLC with reference sorafenib. In an in vivo metabolite analysis [C-11]sorafenib proved to be stable. The percentage of intact product in blood-plasma after 45 min was 90% for [methyl-C-11]-1 and 96% for [urea-C-11]-1, respectively. Due to the more reliable synthesis, further research regarding PET imaging was performed with [methyl-C-11]-1 in nude mice bearing FaDu (head and neck cancer), MDA-MB-231 (breast cancer) or RXF393 (renal cancer) xenografts. Highest tracer accumulation at a level of 2.52 +/- 0.33 %ID/g was observed in RXF393, a xenograft line extensively expressing the sorafenib target antigen Raf-1 as assessed by immunohistochemistry.Conclusion: In conclusion, we have synthesized [C-11]sorafenib as PET tracer, which is stable in vivo and has the capability to be used as PET tracer for imaging in tumor-bearing mice. (C) 2013 Elsevier Inc. All rights reserved.