CN103193867A - 一种18f-rgd多肽及其作为pet显像剂的应用 - Google Patents
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Abstract
Description
(一)技术领域
本发明涉及一种18F-RGD多肽、其合成方法及其作为PET显像剂的应用,可用于对新生血管及肿瘤的PET显像。
(二)背景技术
整合素蛋白家族中的αvβ3在多种肿瘤发生、进展及转移中扮演重要角色,对整合素的表达情况进行可视化及定量对肿瘤诊断及分期、确定治疗方案和监测疗效具有重要意义。
氨基酸序列RGD存在于多种胞外基质蛋白中,可以特异性与整合素结合,因此同位素标记的RGD可用于对整合素的显象。PET是进行活体无损检测的重要工具,很多研究者将RGD短肽进行18F标记,用于整合素的PET显像。
大多数18F标记多肽的方法需要多步反应和多个HPLC纯化步骤,对RGD的标记可以利用18F-SFB和18F-FBA和18F-FBEM等方法,但这些方法都存在时间长、步骤多的缺点,很难实现全自动化,因此难以在临床推广和应用。
基于氟-硅化学,氟-硼化学,以及F-Al配位化学,出现了一些关于多肽的一步18F标记法。我们最近报道了一种基于F-Al配位化学的显像剂18F-AIF-NOTA-RGD2[Liu S,Liu H,Jiang H,Xu Y,Zhang H,Cheng Z.One-step radiosynthesis of 18F-AlF-NOTA-RGD2 for tumorangiogenesis PET imaging.Eur J Nucl Med Mol Imaging.2011,38(9):1732-41],该显像剂的合成时间短,但显像效果一般,其肿瘤/肌肉信号比不高(小于10)。目前另外一种18F标记的RGD显像剂18F-FP-RGD2,其肿瘤/肌肉信号比也小于10,有待改进。
(三)发明内容
本发明要解决的技术问题是提供一种18F-RGD多肽,可作为PET显像剂,用于整合素受体显像,具有高质量的显像结果(肿瘤/肌肉信号大于15)。
本发明采用的技术方案为:
一种18F-RGD多肽,其结构如式(I)所示:
式(I)中,n≥1,优选n的取值在1~12,更优选n的取值为2~5。
本发明式(I)所示的18F-RGD多肽的合成方法包括如下步骤:
a)式(1)所示的1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)先经式(2)所示的1-二甲氨基丙基-乙基碳化二亚胺(EDC)和式(3)所示的N-羟基琥珀酰亚胺磺酸钠盐(SNHS)活化,再与式(II)所示的PEGn-RGD2偶联,经过HPLC纯化得到式(5)所示的NOTA-PEGn-RGD2;
b)18F离子用QMA柱吸附,先用去离子水清洗,再用0.4M KHCO3溶液洗脱,用冰醋酸调节洗脱液的pH到4;
c)在步骤b)处理过的洗脱液中依次加入AlCl3和NOTA-PEGn-RGD2,于100℃反应25分钟;
d)步骤c)所得反应液用去离子水稀释后,经半制备HPLC纯化,收集相应组分并旋干,即得到式(I)所示的产物18F-RGD多肽(18F-AlF-NOTA-PEGn-RGD2)。
式(II)中,n的定义同式(I);
合成路线如下:
本发明中,上述步骤a)至步骤d)的实施可以参照现有技术报道的方法。
本发明所述的18F-RGD多肽可作为PET显像剂,用于整合素受体的显像研究,显像方法包括如下步骤:
1)按照剂量(1~10mCi/kg体重)注射给药;
2)在注射药物后不同时间点在PET或小动物PET仪器进行显像;
3)图像处理及分析。
本发明的优点在于:本发明所述的18F-RGD多肽,其作为PET显像剂,同现有显像剂相比,具有意想不到的显像效果,其肿瘤/肌肉信号比非常高,有良好的应用前景;并且制备条件温和,步骤简便,可实现自动化合成,便于推广。
(四)附图说明
图1是实施例2中,表达整合素αvβ3的荷瘤裸鼠,在注射(1)18F-AlF-NOTA-(PEG)3-RGD2(2)18F-AlF-NOTA-(PEG)3-RGD2和阻断剂c(RGDyK)0.5h,1h,2h后的PET图像。
图2是表达整合素αvβ3的荷瘤裸鼠,在注射显像剂18F-AlF-NOTA-(PEG)3-RGD20.5h,1h,2h后进行PET显像,肿瘤组织与其他组织的信号强度比(肿瘤/肌肉,肿瘤/肝脏,肿瘤/肾脏)。
图3是实施例3中,表达整合素αvβ3的荷瘤裸鼠,在注射(1)18F-AlF-NOTA-(PEG)3-RGD2(2)18F-AlF-NOTA-(PEG)3-RGD2和阻断剂c(RGDyK)2h后显像剂在全身分布情况。
(五)具体实施方式
下面以具体实施例对本发明的技术方案做进一步说明,但本发明的保护范围不限于此:
实施例1:18F-AlF-NOTA-PEG3-RGD2的制备
1)NOTA经EDC和SNHS活化,与PEG3-RGD2偶联,经过HPLC纯化得到NOTA-PEG3-RGD2方法参照文献[Wu Y,Zhang X,Xiong Z,Cheng Z,Fisher DR,Liu S,et al.microPETimaging of glioma integrin{alpha}v{beta}3 expression using(64)Cu-labeled tetrameric RGDpeptide.JNucl Med.2005;46:1707-18.];产率50%,NOTA-PEG3-RGD2分子量测得值为1825.4([M+H]+,分子式C79H121N23O27,计算值1824.94)。HPLC图谱的保留时间为13.8min。
2)30mCi(1.1GBq)18F离子用QMA柱吸附,先用2.5ml去离子水清洗,再用0.4M KHCO3溶液洗脱,用冰醋酸调节洗脱液的pH到4。
3)依次加入AlCl3(2mM,3μL,溶于pH 4的醋酸钠缓冲溶液)和5μL NOTA-PEG3-RGD2(60mg/mL,溶于DMSO),100℃反应15分钟。
4)反应液用1ml去离子水稀释后,经半制备HPLC纯化。半制备HPLC使用Vydac蛋白/多肽柱(218TP510;5μm,250×10mm),Dionex 680HPLC系统,配有UVD170U(Sunnyvale,CA)紫外吸收检测器,和105S放射检测器(Carroll & Ramsey Associates)。流速为4ml/min,梯度洗脱条件如下:0-5min,97vol.%溶剂A[0.1wt.%三氟乙酸(TFA)水溶液]和3vol.%溶剂B[0.1wt.%三氟乙酸的乙腈溶液],5-35min,85vol.%溶剂A和15vol.%溶剂B,35min之后,20vol.%溶剂A和80vol.%溶剂B,产物保留时间为13.7分钟。经组分收集和旋干,得到产物18F-AlF-NOTA-PEG3-RGD2,溶于PBS中,经0.22μm滤膜过滤后用于PET成像。
实施例2:U87MG胶质瘤荷瘤裸鼠进行PET显像研究
U87MG胶质瘤荷瘤裸鼠分别尾静脉注射3.7MBq(100μCi)18F-AlF-NOTA-(PEG)3-RGD2,阻断组还另外注射c(RGDyK)(10mg/kg体重)。在0.5,1,2h三个时间点进行PET扫描,显像结果如图1所示,箭头指示的是肿瘤位置。对显像结果进行定量分析,计算得到肿瘤组织与其他组织的信号强度比(肿瘤/肌肉,肿瘤/肝脏,肿瘤/肾脏),结果如图2。
参考文献[Liu S,Liu H,Jiang H,Xu Y,Zhang H,Cheng Z.One-step radiosynthesis of18F-AlF-NOTA-RGD2for tumor angiogenesis PET imaging.Eur J Nucl Med Mol Imaging.2011,38(9):1732-41]制备显像剂18F-AlF-NOTA-RGD2。按照上述步骤对对照组U87MG胶质瘤荷瘤裸鼠尾静脉注射3.7MBq(100μCi)18F-AlF-NOTA-RGD2,在各时间点进行PET扫描,对照组的显像结果显示,其2小时时间点的肿瘤/肌肉信号比为9.3。
因此,本发明的显像剂18F-AlF-NOTA-(PEG)3-RGD2相比于18F-AlF-NOTA-RGD2具有更高质量的显像结果,尤其是在肿瘤/肌肉信号比上具有显著提高。
实施例3:U87MG胶质瘤荷瘤裸鼠进行生物分布研究
U87MG胶质瘤荷瘤裸鼠分别尾静脉注射3.7MBq(100μCi)18F-AlF-NOTA-(PEG)3-RGD2,阻断组还另外注射c(RGDyK)(10mg/kg体重)。注射2h后测定肿瘤组织及其他组织中的放射含量,结果如图3所示。
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CN106039327A (zh) * | 2016-06-14 | 2016-10-26 | 宁波益格爱生物科技有限公司 | 一种grpr靶向性分子探针及其制备方法 |
CN106083998A (zh) * | 2016-06-08 | 2016-11-09 | 武汉绿海原生物科技有限公司 | 一种有机碱催化巯基‑炔基反应构建多功能小分子探针的方法 |
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Non-Patent Citations (3)
Title |
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SHUANGLONG LIU: "One-step rediosynthesis of 18F-ALF-NOTA-RGD2 for tumor angiogenesis PET imaging", 《EUR J NUCL MED MOL IMAGING》 * |
XIAOYUAN CHEN, ET AL: "Pegylated Arg-Gly-Asp Peptide: 64Cu Labeling and PET Imaging of Brain Tumor αvβ3-Integrin Expression", 《THE JOURNAL OF NUCLEAR MEDICINE》 * |
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CN106083998A (zh) * | 2016-06-08 | 2016-11-09 | 武汉绿海原生物科技有限公司 | 一种有机碱催化巯基‑炔基反应构建多功能小分子探针的方法 |
CN106039327A (zh) * | 2016-06-14 | 2016-10-26 | 宁波益格爱生物科技有限公司 | 一种grpr靶向性分子探针及其制备方法 |
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