CN107405538A - 用于从来源于68Ge/68Ga发生器的洗脱物纯化Ga‑68的工艺和用于所述工艺中的色谱柱 - Google Patents
用于从来源于68Ge/68Ga发生器的洗脱物纯化Ga‑68的工艺和用于所述工艺中的色谱柱 Download PDFInfo
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Abstract
描述了用于纯化来自68Ge/68Ga发生器的洗脱物的色谱柱和使用所述柱的纯化工艺,所述色谱柱包含二氧化硅作为固定相。
Description
发明领域
本发明涉及放射性同位素的纯化工艺,特别是包含来源于68Ge/68Ga发生器的Ga-68的洗脱物的纯化。
现有技术
如已知的,放射性同位素被广泛用于医学中,用于诊断目的和用于治疗目的两者;特别地,金属性质的放射性同位素借助于适当的螯合剂结合至能够识别特定的细胞受体并且与其相互作用(在体内和在体外两者)的载体分子(例如,肽类),以便允许检测和/或破坏病变细胞(diseased cell)。
此标记策略很适合于产生包含载体分子/螯合剂络合物外加以下任何试剂的试剂盒,所述试剂对于允许放射性同位素的螯合是必需的,包含放射性同位素自身的溶液被简单添加至所述试剂,以使标记的分子随时可用。
在核成像中使用的同位素中,Ga-68由于其高的正电子收率(89%)、其有利的半衰期(68min)以及其通过发生器的可用性,是越来越感兴趣的对象,这使得Ga-68不依赖于回旋加速器的存在。此外,由于Ga-68的金属性质,Ga-68可以容易地替代用于治疗的同位素Y-90、In-111以及Lu-177,这向在代谢放射治疗中使用的结合至合适的螯合剂的所有的分子提供诊断对应物。
所有的这些方面可以让位于呈试剂盒形式的新一代放射性药物,该新一代放射性药物可以代表成为Tc-99m在SPECT中的例行使用的基础的方法的PET版本。
然而,在另一方面,尽管Ga-68适合于直接标记并且不依赖于回旋加速器的存在,并且因此是作为可用于制备如上文描述的试剂盒的同位素的候选物,但仍然存在此类方法的成功的障碍。除了与标记条件有关的纯化学方面之外,母体同位素Ge-68可能污染被Ga-68标记的放射性药物的担心强烈地阻碍了基于包含直接来源于Ge68/Ga68发生器的、不被预处理并且不含任何类型的纯化的Ga68的洗脱物的使用的标记策略。
事实上,PET同位素Ga-68来源于的Ge-68/Ga-68发生器是基于Ge-68在固定相上的吸附以及基于通过用溶液洗脱Ga-68分离由母体同位素Ge-68的衰变产生的子同位素Ga-68的可能性,该溶液能够将Ga-68从Ge-68被吸附在其上的固定相中选择性地除去。与此操作相关的风险是,微量的Ge-68可能被释放到用于标记放射性药物化合物的Ga-68的溶液中。
所有这一切导致药物管理部门对于Ge-68从发生器中的释放设定0.001%的最大限值,并且有保留地接收经由试剂盒的标记,该试剂盒基于如由发生器供应而没有可能释放的Ge-68含量的任何纯化或减少的Ga-68溶液的使用。
此外,即使设定上限,也不能保证不存在较高的偶然释放。
当前,将由发生器释放的Ge-68的量最小化,同时在标记之前以在Ga-68放射化学领域中的技术人员已知的不同的方式浓缩并且纯化洗脱物。
因此,清楚的是,当前要解决的最重要的问题是,确保来源于68Ge/68Ga发生器的洗脱物事实上没有Ge-68;并且已经尝试多种解决方案以解决此问题。
这些方法中的一种是基于Ga在阳离子交换树脂上的高分布系数,使得Ga可以仅在被丙酮和HCl的混合物选择性消除母体同位素和其它金属杂质之后被捕获并且然后释放,被丙酮和HCl的混合物选择性消除导致丙酮在洗脱物中的高的百分比。用于基于此策略分离纯化的Ga-68的系统还被授予专利(WO2006/056395)。
然而,此方法具有与使用丙酮以及需要除去有机溶剂和杂质例如异亚丙基丙酮的可能形成有关的某些限制。
可选择的方法使用在浓HCl(>4N)中形成三价Ga的阴离子氯化物GaCl4 -以及其随后在阴离子交换柱上的吸附。在从发生器中洗脱之后,Ga-68的溶液应当通过添加HCl被酸化,并且必须被装载在Ga-68被保留在其上的阴离子交换药筒(anion exchange cartridge)上,并且然后用小体积的水洗脱。在这些条件下,Ge-68不被保留在固定相上。
在此策略的另外的版本(WO 2004/089517)中,描述了具有抗衡离子HCO3 -的阴离子交换器和试剂盒的使用,试剂盒包含发生器、第二阴离子交换柱以及在不同的洗脱步骤中所需要的HCl和水。
阴离子策略还基于:以下设备(US 2009/0001283),所述设备使用泵注射器和各种阀以通过用柠檬酸从发生器柱洗脱Ga-68引导Ge-68与子同位素的分离,;柠檬酸镓到四氯化镓的转化;Ge-68在第二柱上的截留(entrapment)以及用水或稀HCl的最后洗脱。
还描述了用于纯化放射性同位素和形成放射性药物的另一种自动化系统(US2008/0035542),所述自动化系统还能够在阴离子交换树脂上纯化Ga-68时进行预见的步骤的顺序。
最近(WO 2011/033120),与使用浓HCl有关的复杂状态(complication)通过使用氯化物离子的浓溶液(优选地NaCl在HCl 0.1M中的溶液)促进四氯化镓GaCl4 -的形成并且直接在阴离子交换树脂上捕集GaClx络合物来克服。除了减小洗脱物的体积之外,所有的这些方法要求保护还提供从母体同位素Ge-68的有效纯化。
此外,当前合成工艺所需的对标记有Ga-68的产物的固相的最终纯化(通常在C18药筒上进行)还确保进一步减少Ge-68。
因此,当前使用的用Ga-68的标记方法是基于多步工艺,该多步工艺包括发生器的洗脱物的预纯化(prepurification)(阴离子的、阳离子的或通过分馏)以及在C18药筒上纯化最终标记的产物。
需要所有的这些步骤以通过浓缩反应体积和消除未反应的Ga-68来改进标记有Ga-68的结果。
作为平行的结果,它们还产生可能由发生器释放的Ge-68的减少。
清楚的是,不存在Ge-68的包含Ga-68的洗脱物的可用性将使得上文描述的工艺步骤不必要,因此不存在Ge-68的包含Ga-68的洗脱物允许直接地并且以接近100%的收率标记试剂盒,而不需要在标记之前减小洗脱物的体积或在标记结束时消除未反应的Ga-68。
发明概述
本发明允许通过完全逆转用于当前标记方法中的逻辑来解决上文的问题,其中Ga-68首先被捕集在特定的柱上,以允许通过随后的洗涤除去可能的污染物,并且然后以减小的体积回收以用于标记反应。
发明详述
根据本发明的工艺允许在一个步骤中捕集Ge-68,Ge-68需要从来自发生器的输出中的洗脱物中消除,并且从而直接使用来源于发生器的Ga-68的溶液,以用于标记试剂盒的重构,而没有另外的处理或步骤。
根据本发明的工艺,通过在洗脱物从发生器流动至容纳如上文描述的标记试剂盒的容器的同时允许直接捕集Ge-68,允许类似于Tc-99m所发生的Ga-68的蔓延(spread)加宽。
为了实现上文,根据本发明的工艺使用包含合适的固定相的柱,该柱放置在发生器输出线处,充当用于Ge-68的捕集器(trap)。
事实上,令人惊讶地发现,二氧化硅能够发挥捕集Ge-68并且使Ga68在发生器的洗脱物通过的同时自由通过而不需要洗涤和洗脱步骤的双重作用,这防止使标记程序复杂化或延长,允许在将洗脱物添加至试剂盒的同时有效纯化。
应当注意,尽管二氧化硅作为固定相用于色谱纯化是熟知的,但二氧化硅从未被用于在来自Ge-68/Ga-68发生器的洗脱物的放射性核素纯化中捕集Ge-68,也不能被预期对来源于68Ge/68Ga发生器的洗脱物的组分施加如上文描述的双重作用,并且在另一方面,通常用作用于色谱纯化柱的固定相的其他材料不能够进行相同的作用。
特别地,为了在根据本发明的工艺中是有效的,二氧化硅必须具有不高于250微米、优选地小于100微米的粒度(granulometry)。用具有小于50微米、优选地包括在20和10微米之间的粒度的二氧化硅获得最优的结果。
因此,此类型的二氧化硅可以被用于制备用于根据本发明的工艺的色谱柱,该色谱柱直接地连接至根据用于本领域中的标准制备技术的68Ge/68Ga发生器。
特别地,根据本发明,可以制备一次性柱,其中二氧化硅的量在2g和200mg之间。所述柱被放置在发生器的输出处,以从Ge-68纯化Ga-68的溶液。
通过使从Ge-68/Ga-68发生器洗脱的放射性溶液通过由此制备的柱,仅可忽略量的Ga-68仍然保留在柱中,同时几乎所有的Ge-68仍然被捕集,从而允许获得洗脱物,该洗脱物完全满足针对具有Ga68的标记试剂盒的规定所需要的纯度需求。
应当注意,根据本发明的柱按照原样保留存在于洗脱物中的Ge-68,而不需要改变pH或组成,以便允许直接回收纯化的Ga-68溶液,避免中间的稀释步骤、浓缩步骤和/或转移步骤。Ge-68通过在专用的药筒上简单通过的截留不使标记程序复杂化或延长,这提供放射性核素纯化连同发生器的洗脱。
应当注意,使用这样的药筒提供制备试剂盒的可能性,所述试剂盒允许通过将来源于发生器的洗脱物直接添加至被标记的底物而用Ga-68标记,而没有任何其他的附属操作。
实施例1
Ga-68在HCl 0.1N中的溶液的纯化
将设置有聚乙烯分隔物(polyethylene partition)的10个空的塑料柱装载有具有20-10微米的粒度的650mg的药物级二氧化硅。
在基于TiO2的Ge-68/Ga-68发生器的10个洗脱测试中,在没有任何洗涤或预调节(pre-condition)的情况下使用由此获得的药筒。
将每个柱连接至发生器的输出,并且将通过用5ml的HCl 0.1N洗脱发生器获得的Ga-68的溶液直接收集在瓶中。
立即测量Ga-68在洗脱物中和在药筒中的活性,同时在通过HP-Geγ光谱法测量Ge-68的含量之前将样品留下衰变持续2天。
在10个测试中,被柱保留的Ga-68的平均活性是3%,而保留的Ge-68的活性平均是由发生器释放的总量的90%。
实施例2
Ga-68在HCl 0.05N中的溶液的纯化
将设置有聚乙烯分隔物的10个空的塑料柱装载有具有20-10微米的粒度的650mg的药物级二氧化硅。
在基于有机树脂的Ge-68/Ga-68发生器的10个洗脱测试中,在没有任何洗涤或预调节的情况下使用所得到的药筒。
将每个柱连接至发生器的输出,并且将通过用5ml的HCl 0.05N洗脱发生器获得的Ga-68的溶液直接收集在瓶中。
立即测量Ga-68在洗脱物中和在药筒中的活性,同时在HP-Geγ光谱法测量Ge-68的含量之前,将样品留下衰变持续2天。
在10个测试中,被柱保留的Ga-68的平均活性是4%,保留的Ge-68的活性平均是由发生器释放的总量的95%。
Claims (10)
1.用于纯化来源于68Ge/68Ga发生器的洗脱物的色谱柱,其中所述色谱柱包括能够保留Ge-68同时允许洗脱所述Ga-68的固定相。
2.根据权利要求1所述的色谱柱,其中所述固定相是具有不高于250微米的粒度的二氧化硅。
3.根据权利要求2所述的色谱柱,其中所述二氧化硅具有小于100微米的粒度。
4.根据权利要求3所述的色谱柱,其中所述二氧化硅具有小于50微米、优选地包括在20和10微米之间的粒度。
5.根据权利要求1-4所述的色谱柱,其中所述柱是一次性柱。
6.用于纯化来自68Ge/68Ga发生器的洗脱物的工艺,其特征在于,使用根据权利要求1-4的色谱柱。
7.根据权利要求6所述的工艺,其中:
-根据权利要求1-5的色谱柱被放置在所述发生器的出口处;
-来自所述发生器的所述溶液被允许流过所述柱;
-包含放射性Ga-68的纯化的溶液被收集在所述柱的所述出口处。
8.根据权利要求7所述的工艺,其中所述柱是一次性柱。
9.用于制备包含Ga-68的放射性标记的工艺,其中通过根据权利要求7和8所述的工艺获得的纯化的溶液被直接地倾倒在容纳形成所述放射性标记试剂盒的其他产物的所述容器中。
10.放射性标记试剂盒,其中用于所述放射性标记的放射性同位素是通过根据权利要求7和8所述的工艺产生的Ga-68。
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