CN103980297B - 一种检测汞离子的多功能成像探针 - Google Patents

一种检测汞离子的多功能成像探针 Download PDF

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CN103980297B
CN103980297B CN201410148145.6A CN201410148145A CN103980297B CN 103980297 B CN103980297 B CN 103980297B CN 201410148145 A CN201410148145 A CN 201410148145A CN 103980297 B CN103980297 B CN 103980297B
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张晓琳
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Abstract

本发明涉及一种检测汞离子的多功能成像分子探针。该探针具有如下结构通式：制备时，先以等摩尔量的罗丹明为原料，与五倍量的乙二胺于乙醇中加热反应，得到白色固体。然后在二甲基甲酰胺溶液中，将白色固体进一步与二乙烯三胺五乙酸二酐加热反应，减压干燥，得到的产品与硝酸钆在甲醇溶液中常温搅拌过夜，减压干燥得到目标产物。该探针分子具有较好的化学、光稳定性，易溶于水中，较高的汞离子选择性，不受其他生物体内的金属离子干扰，能实现汞离子高灵敏度的荧光成像和高空间分辨率的磁共振成像。

Description

一种检测汞离子的多功能成像探针
技术领域
本发明涉及一类用荧光成像和磁共振成像检测汞离子的多功能成像分子探针。
背景技术
由于汞具有高度的化学反应活性，它能与体内酶、蛋白质和核酸等生物分子中的羧基、巯基和磷酸基等官能团发生缔合，这使神经子传递和细胞分裂等生命过程受到了严重干扰，对人类健康构成了巨大的威胁。而对于汞元素在生物体内发生作用的机理，人们至今仍未能清楚的了解。因此，一个有效的汞元素分析检测手段，尤其是能多方位多层次集多种成像方式于一体的汞元素检测方法，对我们进一步了解汞元素的作用机理，从而避免汞的危害以及污染源的控制管理提供了必要的依据。
荧光成像方法由于其实时方便，检测灵敏度高，靶向性好，在汞离子的检测上独具优势。国际以及国内多家科研机构利用荧光探针对汞离子检测上做了许多开创性的工作，为汞离子的高灵敏度检测奠定了坚实的基础。但荧光成像受制于其有限的组织穿透力，只能实现较好的体外成像，在生物体的应用仍是困难重重。而磁共振成像的自身特点决定了其具备荧光等许多成像方式所不具备的高空间分辨率优势，弥补了荧光成像的穿透力的缺陷。但目前磁共振成像技术面临着应用瓶颈，即灵敏度低，造影的靶向性差。而将荧光成像和磁共振成像集于一个分子的多功能成像模式能很好地实现了两种成像模式的优势互补，使汞离子的成像即具有荧光成像的高灵敏度又兼具了磁共振成像的高空间分辨率。开发用荧光成像和磁共振成像多功能成像模式检测汞离子的分子探针不仅弥补了两种成像方式的不足，也实现了汞离子的多方位多层次丰富影像表征，为汞离子所引起的重大疾病的预防和早期诊断提供更多有价值的信息。
发明内容
本发明提供了一类检测汞离子的集荧光成像和磁共振成像功能于一身的多功能成像探针。其结构通式如（I）所示：
（I） 。
本发明的目的之二是提供如下的方法来实现：
该探针的合成方法按如下步骤进行：
a、以罗丹明类化合物和过量的乙二胺为原料，溶解于乙醇中，加热至80℃，反应四小时后，将反应液静置，抽滤，减压干燥，得到白色固体。（罗丹明类似物可以是罗丹明B或罗丹明6G）。
b、将a步骤得到的白色固体溶解于二甲基甲酰胺（DMF）溶液中，加入0.5倍摩尔量的二乙烯三胺五乙酸二酐(下面简称DTPA)，于油浴中加热六小时，确定原料反应完毕，减压蒸出DMF，减压干燥，得到白色固体。
c、将b步骤得到的白色固体和等摩尔量的硝酸钆溶解于甲醇中，常温下搅拌24小时，减压干燥得到目标产物。
上述基于罗丹明和DP3A的多功能成像探针的制备反应式如下：
本发明的汞离子多功能成像探针用于荧光成像方式和磁共振成像方式来检测汞离子。
本发明的有益效果是：
该探针的荧光响应部分采用的罗丹明荧光团具有较高的荧光量子产率，良好的化学稳定性，而采用的磁共振响应部分的配体DP3A对钆离子有较高的结合常数，在溶剂中具有较好的稳定性；探针分子对汞离子具有较高的选择性，其他生物体内的离子如锌离子、铜离子、钙离子等对其无干扰，并且还具有较高的灵敏度。
本发明的重要贡献在于合成了两种检测汞离子的多功能成像分子，通过将高灵敏度的荧光成像和高空间分辨率的磁共振成像结合，即避免了传统的荧光成像探针对组织穿透力差的缺陷，又弥补了磁共振成像的低灵敏度，实现了两类成像方式的优势互补；本发明中探针的设计机理是通过罗丹明化合物与汞离子的化学反应来实现汞离子的检测，并且合理的调节连接基团，引入磁共振成像检测单元，实现了多层次多方位的汞离子成像。
附图说明
图 1 是本发明中多功能成像探针（实施例1c）的质谱。
图 2 是本发明中多功能成像探针（实施例1c）对汞离子响应的荧光光谱。
具体实施方式
实施例 1
a罗丹明B溶解于乙醇中，向溶液中加入五倍摩尔量的乙二胺，搅拌下加热至80℃，反应四小时后，将反应液静置，抽滤，减压干燥，得到白色固体，产率90%，HRMS 484.2838；
b将a步骤得到的白色固体溶解于DMF溶液中，加入0.5倍摩尔量的DTPA，于油浴100度中加热六小时，减压蒸出DMF，减压干燥，得到白色固体，收率95%，HRMS 1325.6849；
c将b步骤得到的白色固体和等摩尔量的硝酸钆溶解于甲醇中，常温下搅拌24小时，减压干燥得到目标产物，收率95%, TOF-ESI-MS: calcd for [C74H88GdN11O12+2H]2+：m/z 741.2997, found m/z 741.0806; calcd for [C74H88GdN11O12+H+Na] 2+：m/z752.2904, found m/z 752.0723。
实施例 2
a工序中用罗丹明B代替罗丹明6G，其余同实例1, TOF-ESI-MS: calcd for[C70H80GdN11O12+2H]2+：m/z 713.2615, found m/z 713.2623。

Claims (3)

1.一种检测汞离子的多功能成像探针，其特征在于，该探针具有如下结构通式：
（I）。
2.根据权利要求1所述的一种检测汞离子的多功能成像探针的合成方法，包括如下步骤：
a、以罗丹明类化合物和过量的乙二胺为原料，溶解于乙醇中，加热至80℃，反应四小时后，将反应液静置，抽滤，减压干燥，得到白色固体；
b、将a步骤得到的白色固体溶解于二甲基甲酰胺（DMF）溶液中，加入0.5倍摩尔量的二乙烯三胺五乙酸二酐(DTPA)，于油浴中加热六小时，减压蒸出DMF，减压干燥，得到白色固体；
c、将b步骤得到的白色固体和等摩尔量的硝酸钆溶解于甲醇中，常温下搅拌24小时，减压干燥得到目标产物；
所述的罗丹明类化合物是罗丹明6G或罗丹明B。
3.权利要求1所述的一种检测汞离子的多功能成像探针的应用，其特征在于，该探针用于化学模拟生理体系中汞离子的检测，其荧光随着汞离子的加入逐渐增强。
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