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MRI对比剂Gd-DO3A-Ether-Rhein的合成及其坏死亲和性研究

Synthesis and evaluation of necrosis avidity of MRI contrast agent Gd-DO3A-Ether-Rhein

  • 摘要: 以大黄酸为底物、醚链为连接臂合成磁共振成像(MRI)对比剂并评价其坏死亲和性。合成新的配体10-[6-(1,8-二羟基蒽醌-3-甲酰氨基)乙氧基乙基]氨基羰酰甲基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A-Ether-Rhein,即E1),再与Gd3+配位得到顺磁性对比剂10-[6-(1,8-二羟基蒽醌-3-甲酰氨基)乙氧基乙基]氨基羰酰甲基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸合钆(Gd-DO3A-Ether-Rhein,即GdE1)。分别在高热诱导的人肝癌HepG2细胞坏死模型和微波消融诱导的大鼠肌肉坏死模型上评价探针的坏死亲和性。动物试验中,分别在给予GdE1(0.1 mmol/kg)前和给药后0~9 h进行MRI成像,Gd-DOTA(1,4,7,10-四乙酸-1,4,7,10-四氮杂环十二烷合钆)作为对照。MRI成像结果表明,坏死细胞的信号强度(4 369±70)显著高于正常细胞(2 555±84)(P<;0.05);在GdE1给药后3 h,坏死肌肉与正常肌肉的对比度为2.00±0.12,显著高于给药后0 h(1.27±0.03)(P<;0.05)。上述结果表明,GdE1具有良好的坏死亲和性,在坏死相关疾病的诊断上显示出良好的应用潜力。

     

    Abstract: The aim of this study was to synthesize and evaluate the necrosis avidity of MRI contrast agent based on rhein and linked by ether. The novel ligand 10-[6-(1, 8-dihydroxyanthraquinone-3-carboxamido)ethoxyethyl]aminocarbonylmethyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetic acid(DO3A-Ether-Rhein, E1)was synthesized by two steps of acylation and deprotection reaction. The paramagnetic gadolinium 10-[6-(1, 8-dihydroxyanthraquinone-3-carboxamido)ethoxyethyl]aminocarbonylmethyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetic acid(Gd-DO3A-Ether-Rhein, GdE1)was obtained by coordination of Gd3+ with the above ligand. We examined the necrotic avidity of GdE1 in human hepatocellular carcinoma HepG2 cell necrosis induced by hyperthermia in vitro and in rat model with muscular necrosis induced by microwave ablation in vivo by MRI. The MRI was implemented before administration of GdE1 and during 0-9 h after administration of GdE1(0. 1 mmol/kg), and Gd-DOTA(gadolinium 1, 4, 7, 10-tetraacetic acid-1, 4, 7, 10-tetraazacyclo dodecane)was used as control. The signal intensity of necrotic cells(4 369±70)was significantly higher than that of normal cells(2 555±84)(P< 0. 05). Similarly, the contrast ratio between necrotic and normal muscle at 3 h after administration of GdE1(2. 00±0. 12)was remarkblely higher than that at 0 h after administration of GdE1(1. 27±0. 03)(P< 0. 05). Therefore, GdE1 presents good necrosis affinity and has the potential to be used in the diagnosis of necrosis-related diseases.

     

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