CN113144225A - 一种高放射性核纯度的68Ga-GaCl3溶液的制备方法及应用 - Google Patents
一种高放射性核纯度的68Ga-GaCl3溶液的制备方法及应用 Download PDFInfo
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Abstract
本发明提供一种高放射性核纯度的68Ga‑GaCl3溶液的制备方法及应用。该制备方法通过:以68Zn‑Zn(NO3)2溶液为靶材,利用质子轰击68Zn‑Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。本发明利用质子轰击68Zn‑Zn(NO3)2液体靶生产正电子核素68Ga,经分离纯化后获得可用于正电子放射性药物生产标记的68GaCl3溶液,并且其化学指标与商业获得的一致,为我国制定68Ga放射性药物的质量标准提供了依据。并且该放射性标记物可以直接用于PSMA、FAPI、BBN等标记小分子药物以及标记多肽示踪剂,促进了68Ga标记放射性药物在广东地区的研究与广泛应用。
Description
技术领域
本发明涉及放射医学技术领域,具体涉及一种高放射性核纯度的68Ga-GaCl3溶液的制备方法及应用。
背景技术
正电子发射计算机断层(PET)显像已广泛应用于疾病临床诊断和疗效评价。有关正电子核素68Ga的研究可追溯至20世纪50年代末,早期发展缓慢;随着技术的进步,2000年以后相关研究逐渐增多,并在2010年左右出现爆发式增长。目前68Ga在PET显像中的应用仅次于18F。68Ga由68Ge/68Ga发生器生产。68Ge/68Ga发生器中68Ge的半衰期是270.8d,制备所得68Ga的物理半衰期为67.71min,在衰变过程中的正电子衰变率占89%,Emax为1.92MeV,剩余的11%为电子俘获,适用于标记小分子药物的药代动力学研究以及标记多肽示踪剂。较短的半衰期有效降低了病人承受的辐照剂量,同时也给核医学化学师足够的制备时间,便于推广应用。
现有68Ga都是通过68Ge-68Ga锗镓发生器制备获得,价廉易得,可与单光子发射计算机断层显像(SPECT)中应用最为广泛的99mTc媲美。与99mTc相比,68Ga显像具有更高的灵敏度和空间分辨率,且可以定量,预计在不久的将来将会取代部分99mTc药物。与18F、11C等非金属核素传统标记多肽等生物小分子相比,68Ga标记具有方法简便快速、条件温和、便于药盒化等优点,且成本低廉,适合普及推广。随着68Ge/68Ga发生器相关技术的日趋成熟、蛋白质/多肽类示踪剂配位化学标记技术的进步、蛋白质组学和基因组学的发展以及对疾病特定生物化学过程关键化合物的掌握,促进了68Ga标记示踪剂在全球的广泛研究与应用。近几年,国内数家单位陆续引进68Ge/68Ga发生器,并在68Ga标记显像剂临床应用方面作出了可喜的成绩。然而,68Ga标记药物的临床应用长期受制于锗镓发生器的68Ge漏穿及淋洗液不纯等问题,近年来,药物级锗镓发生器获批投入市场,生产68Ga纯度虽有大幅度提高,但仍无法解决产生68Ge漏穿和杂质离子的问题。另外,锗镓发生器一次淋洗68Ga放射性有限,用于一次标记药物只能满足3-5个患者PET显像需要,完全不能满足68Ga产业化生产和标记及其临床诊断的需要。
目前,镓-68可以通过两种不同的方法得到的。第一种是最常用的方法,即上文介绍的Ge-68/Ga-68发生器系统,68Ge是68Ga的母体同位素,半衰期为270.8天(约9个月),这种发生器系统易洗提,并且提取的Ga-68直接用于放射性药物的标记,但主要问题就是存在68Ge漏穿及淋洗液不纯。第二种方法,由于其复杂性和非常昂贵的费用而较少使用,即利用回旋加速器通过质子轰击固体Zn-68靶质子来生产68Ga,利用高能量的质子轰击68Zn核,经该过程形成68Ga核素并释放中子,相应的核反应可表示为68Zn(p,n)68Ga。68Ga回旋加速器生产后的另一个重要步骤是回收再利用68Zn靶,从固体靶上洗脱68Ga,利用树脂纯化中洗脱溶液,通过加热蒸发,剩下的残留物溶解在HCl溶液中,并置于阴离子交换色谱柱中。虽然这种方法可以获得较高的产率,但其过程是一个缓慢、复杂和昂贵的工艺。因此,有必要开发更为简单并经济的高放射性核纯度的68Ga-GaCl3制备技术。
发明内容
针对现有技术存在的问题,本发明旨在提供一种高放射性核纯度的68Ga-GaCl3溶液的制备方法及应用。本发明的技术方案为:
第一个方面,本发明提供一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,通过:以68Zn-Zn(NO3)2溶液为靶材,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。
进一步地,所述制备方法具体包括:
步骤一,采用68Zn-Zn(NO3)2溶液填充靶,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应得到68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液;
步骤二,采用强阳离子交换柱对步骤一获得的68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液进行纯化,得到68Ga-GaCl3溶液。
进一步地,所述步骤一的控制参数为:轰击束流为35μA~45μA,加速能量为14MeV~16MeV,轰击时间小于90分钟。
进一步地,所述步骤二的控制参数为:所选用的阳离子交换柱以苯乙烯-二乙烯基苯聚合物为基质,键合苯磺酸作为固定相,以氢离子作为交换平衡离子。以0.5~0.84M的氢溴酸丙酮水溶液作为杂质洗脱液,并以3M以上的HCl溶液作为68Ga的洗脱液。
第二个方面,本发明提供一种68Ga-GaCl3溶液,是采用上述制备方法获得。
第三个方面,本发明提供上述68Ga-GaCl3溶液在放射性标记上的应用。
进一步地,所述应用为在标记NOTA-BBN上的应用。
本发明的有益效果总结如下:
1、本发明填补了国内利用液体靶生产金属同位素标记物的空白。
2、本发明利用质子轰击68Zn-Zn(NO3)2液体靶生产正电子核素68Ga,经分离纯化后获得可用于正电子放射性药物生产标记的68GaCl3溶液,并且其化学指标与目前已经商业化的68Ga一致,其核纯度如图1,为我国制定68Ga放射性药物的质量标准提供了依据。
3、经本发明制备的Ga-68标记物标记放射性药物,能有效提高PET诊断的准确性。
4、本发明解决了68Ga标记药物的临床应用长期受制于锗镓发生器的68Ge漏穿及淋洗液不纯等问题,直接生产的68GaCl3用于FAPI、BBN等标记小分子药物以及标记多肽示踪剂,促进了68Ga标记放射性药物在广东地区的研究与广泛应用。
附图说明
图1为68Ge/68Ga发生器制备的68GaCl3和本发明实施例1所制备的68GaCl3的核纯度对比。
具体实施方式
在本发明的描述中,需要说明的是,实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
下面结合附图和具体的实施例对本发明做进一步详细说明,所述是对本发明的解释而不是限定。
实施例1
本实施例提供一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,通过:以68Zn-Zn(NO3)2溶液为靶材,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。具体包括以下步骤:
(1)采用68Zn-Zn(NO3)2溶液填充靶,利用质子轰击68Zn-Zn(NO3)2液体靶,轰击束流为40μA,加速能量为15MeV,轰击时间为1h。经68Zn(p,n)68Ga核反应得到68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液;
(2)采用强阳离子交换柱对步骤一获得的68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液进行纯化,所选用的阳离子交换柱以苯乙烯-二乙烯基苯聚合物为基质,键合苯磺酸作为固定相,以氢离子作为交换平衡离子。以0.84M的氢溴酸丙酮水溶液作为杂质洗脱液,然后以3M的HCl溶液作为68Ga的洗脱液,30min内即可得到68Ga-GaCl3溶液,产量达130mCi,核纯度为99.7%。本实施例获得的68Ga-GaCl3溶液的核纯度结果与对比例1进行了比较,结果如图1所示,表明本实施例获得的68Ga-GaCl3溶液的核纯度与现有市售68Ge/68Ga发生器制备的68Ga-GaCl3溶液核纯度相当。
实施例2
本实施例提供一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,通过:以68Zn-Zn(NO3)2溶液为靶材,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。具体包括以下步骤:
(1)采用68Zn-Zn(NO3)2溶液填充靶,利用质子轰击68Zn-Zn(NO3)2液体靶,轰击束流为35μA,加速能量为14MeV,轰击时间为70min。经68Zn(p,n)68Ga核反应得到68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液;
(2)采用强阳离子交换柱对步骤一获得的68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液进行纯化,所选用的阳离子交换柱以苯乙烯-二乙烯基苯聚合物为基质,键合苯磺酸作为固定相,以氢离子作为交换平衡离子。以0.84M的氢溴酸丙酮水溶液作为杂质洗脱液,然后以3M的HCl溶液作为68Ga的洗脱液,30min内即可得到68Ga-GaCl3溶液,产量达136mCi,核纯度为99.9%。。
实施例3
本实施例提供一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,通过:以68Zn-Zn(NO3)2溶液为靶材,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。具体包括以下步骤:
(1)采用68Zn-Zn(NO3)2溶液填充靶,利用质子轰击68Zn-Zn(NO3)2液体靶,轰击束流为45μA,加速能量为16MeV,轰击时间为50min。经68Zn(p,n)68Ga核反应得到68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液;
(2)采用强阳离子交换柱对步骤一获得的68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液进行纯化,所选用的阳离子交换柱以苯乙烯-二乙烯基苯聚合物为基质,键合苯磺酸作为固定相,以氢离子作为交换平衡离子。以0.5M的氢溴酸丙酮水溶液作为杂质洗脱液,然后以3M的HCl溶液作为68Ga的洗脱液,30min内即可得到68Ga-GaCl3溶液,产量达115mCi,核纯度为99.7%。
实施例4
68Ga-NOTA-BBN的标记,具体标记方法如下:
用10mL玻璃瓶收集2mL实施例1获得的68GaCl3溶液,向溶液中加150μL的NaOAc(1.25M)溶液调pH至4,再加入100μL 1M HEPES溶解的DOTA\NOTA-BBN(15μg,10nmol)溶液。反应混合液在95~100℃反应10min后,冷却反应,向反应液中加入10mL的水稀释后过plusC18柱,产物吸附在plus C18,再用5mL的水洗plus C18柱,洗去残留的68GaCl3和无机化合物。用乙醇(2mL)洗脱plus C18柱得到产物68Ga-NOTA-BBN,在氮气流下,减压除去乙醇后,加入PBS配成的溶液,通过0.22μm无菌滤膜后使用。68Ga-DOTA\NOTA-BBN未衰变校正的标记产率为50%,放射标记总时间是25min,比活度是1.1×1010Bq/mmol;放射性纯度大于95%。
液相色谱仪(shimadzu),HPLC分析条件:分析柱InertSustainC18(5μm,4.6×150mm),梯度洗脱:0-2min时,0.1%TFA的乙腈溶液/0.1%TFA的水溶液:5/95;逐渐升到25min时,0.1%TFA的乙腈溶液/0.1%TFA的水溶液:80/20。流速为1mL/min,紫外检测波长220nm。
获得的68Ga-NOTA-BBN注射液,依据并参照欧洲药典(3109)标准和我国的放射性药物质量保证标准,对68GaCl3溶液和68Ga-NOTA-BBN注射液进行了相应的质量检验,也制定了68Ga-NOTA-BBN注射液的pH值、放射性核素纯度、放射性化学纯度和化学纯度等企业质量标准,最终产品完全符合我国药典关于放射性药品的规范要求。
对比例1
将市售的68Ge/68Ga发生器制备68Ga-GaCl3溶液进行核纯度检测,结果如图1所示,该68Ga-GaCl3溶液由广州原子高科股份有限公司提供。
综上所述,本发明利用质子轰击68Zn-Zn(NO3)2液体靶生产正电子核素68Ga,经分离纯化后获得可用于正电子放射性药物生产标记的68GaCl3溶液,该68GaCl3溶液化学指标与商业获得的一致,可以直接用于FAPI、BBN等标记小分子药物以及标记多肽示踪剂。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (7)
1.一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,其特征在于:通过:以68Zn-Zn(NO3)2溶液为靶材,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应获得。
2.权利要求1所述的一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,其特征在于:所述制备方法具体包括:
步骤一,采用68Zn-Zn(NO3)2溶液填充靶,利用质子轰击68Zn-Zn(NO3)2液体靶,经68Zn(p,n)68Ga核反应得到68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液;
步骤二,采用强阳离子交换柱对步骤一获得的68Ga-Ga(NO3)3/68Zn-Zn(NO3)2混合液进行纯化,得到68Ga-GaCl3溶液。
3.根据权利要求2所述的一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,其特征在于:所述步骤一的控制参数为:轰击束流为35μA~45μA,加速能量为14MeV~16MeV,轰击时间小于90分钟。
4.根据权利要求2所述的一种高放射性核纯度的68Ga-GaCl3溶液的制备方法,其特征在于:所述步骤二的控制参数为:所选用的阳离子交换柱以苯乙烯-二乙烯基苯聚合物为基质,键合苯磺酸作为固定相,以氢离子作为交换平衡离子。以0.5~0.84M的氢溴酸丙酮水溶液作为杂质洗脱液,并以3M以上的HCl溶液作为68Ga的洗脱液。
5.一种68Ga-GaCl3溶液,其特征在于:是采用权利要求1~4任意一项所述的制备方法获得。
6.权利要求5所述的68Ga-GaCl3溶液在放射性标记上的应用。
7.根据权利要求6所述的应用,其特征在于:所述68Ga-GaCl3溶液在标记NOTA-BBN上的应用。
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