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Synthesis and biological evaluation of a novel Tc-99m cyclopentadienyl tricarbonyl complex ([(Cp-R)Tc-99m(CO)(3)]) for sigma-2 receptor tumor imaging
Chen, Xin1; Cui, Meng-Chao1; Deuther-Conrad, Winnie2; Tu, Ying-Feng3; Ma, Teng4; Xie, Ying3; Jia, Bing4; Li, Yan1; Xie, Fang1; Wang, Xia1; Steinbach, Joerg2; Brust, Peter2; Liu, Bo-Li1; Jia, Hong-Mei1
关键词Sigma-2 Receptor Imaging Agent Cyclopentadienyl Tricarbonyl Complex Tc-99m
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
2012-10-15
DOI10.1016/j.bmcl.2012.08.083
22期:20页:6352-6357
收录类别SCI ; IC
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Medicinal ; Chemistry, Organic
研究领域[WOS]Pharmacology & Pharmacy ; Chemistry
关键词[WOS]PROTEIN-KINASE INHIBITORS ; CHEMICAL SPACE ; BREAST-CANCER ; LIGAND ; DERIVATIVES ; CLONING ; AGENT ; 1-CYCLOHEXYLPIPERAZINE ; EXPRESSION ; ANALOGS
英文摘要

We report the design, synthesis and biological evaluation of a novel Tc-99m 4-(4-cyclohexylpiperazine-1-yl)-butan-1-one-1-cyclopentadienyltricarbonyl technetium ([Tc-99m]5) as a potential SPECT tracer for imaging of sigma(2) receptors in tumors. [Tc-99m]5 was prepared in 25 +/- 5% isolated radiochemical yield with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the ferrocene precursor 2b (4-(4- cyclohexylpiperazine- 1-yl)-1-ferrocenylbutan-1-one). The corresponding Re-complex 4 and the ferrocenyl complex 2b showed relatively high affinity towards sigma(2) receptors in in vitro competition binding assay (K-i values of 4 and 2b were 64.4 +/- 18.5 nM and 43.6 +/- 21.3 nM, respectively) and moderate to high selectivity versus sigma(1) receptors (K-i sigma(1)/K-i sigma(2) ratios were 12.5 and 95.5, respectively). The logD value of [Tc-99m] 5 was determined to be 2.52 +/- 0.33. Biodistribution studies in mice revealed comparably high initial brain uptake of [Tc-99m]5 and slow washout. Administration of haloperidol 5 min prior to injection of [Tc-99m]5 significantly reduced the radiotracer uptake in brain, heart, lung, and spleen by 40-50% at 2 h p.i.. Moreover, [Tc-99m]5 showed high uptake in C6 glioma cell lines (8.6%) after incubation for 1 h. Blocking with haloperidol to compete with [Tc-99m]5 significantly reduced the cell uptake. Preliminary blocking study in C6-brain-tumor bearing rats showed that [Tc-99m]5 binds to r receptors in the brain-tumor specifically. These results are encouraging for further exploration of Tc-99m-labeled probes for sigma(2) receptor tumor imaging in vivo. (c) 2012 Elsevier Ltd. All rights reserved.

语种英语
WOS记录号WOS:000309609500008
项目编号21071023
资助机构National Natural Science Foundation of China ; Fundamental Research Funds for the Central Universities
引用统计
被引频次:19[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54857
专题北京大学药学院_药剂学系
北京大学基础医学院
作者单位1.Beijing Normal Univ, Coll Chem, Minist Educ, Key Lab Radiopharmaceut, Beijing 100875, Peoples R China
2.Helmholtz Zentrum Dresden Rossendorf, Inst Radiopharm, Neuroradiopharmaceut Div, D-04318 Leipzig, Germany
3.Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
4.Peking Univ, Sch Basic Med Sci, Dept Radiat Med, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Chen, Xin,Cui, Meng-Chao,Deuther-Conrad, Winnie,et al. Synthesis and biological evaluation of a novel Tc-99m cyclopentadienyl tricarbonyl complex ([(Cp-R)Tc-99m(CO)(3)]) for sigma-2 receptor tumor imaging[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2012,22(20):6352-6357.
APA Chen, Xin.,Cui, Meng-Chao.,Deuther-Conrad, Winnie.,Tu, Ying-Feng.,Ma, Teng.,...&Jia, Hong-Mei.(2012).Synthesis and biological evaluation of a novel Tc-99m cyclopentadienyl tricarbonyl complex ([(Cp-R)Tc-99m(CO)(3)]) for sigma-2 receptor tumor imaging.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,22(20),6352-6357.
MLA Chen, Xin,et al."Synthesis and biological evaluation of a novel Tc-99m cyclopentadienyl tricarbonyl complex ([(Cp-R)Tc-99m(CO)(3)]) for sigma-2 receptor tumor imaging".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22.20(2012):6352-6357.
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