CN113861254B - 一种肿瘤PET显像剂68Ga-NOTA-ADG及其制备方法和应用 - Google Patents
一种肿瘤PET显像剂68Ga-NOTA-ADG及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种肿瘤PET显像剂68Ga‑NOTA‑ADG及其制备方法和应用,涉及PET显像剂68Ga‑NOTA‑ADG的标记前体的合成和68Ga‑NOTA‑ADG的放射性合成,其中,前体是第一次用于68Ga‑NOTA‑ADG的标记,结果显示该制备方法放射化学产率接近100%。本发明的正电子显像剂68Ga‑NOTA‑ADG能够作为靶向肿瘤的PET显像探针。因此,使得68Ga‑NOTA‑ADG成为肿瘤的PET候选显像探针。本发明首次进行了68Ga‑NOTA‑ADG放射性化学合成,制备方法简单快捷,为68Ga‑NOTA‑ADG的科学研究和临床应用奠定了基础。
Description
技术领域
本发明涉及放射性药物化学技术领域,具体涉及一种肿瘤PET显像剂68Ga-NOTA-ADG及其制备方法和应用。
背景技术
近日,世界卫生组织国际癌症研究机构(IARC)发布了最新的2020年全球癌症负担数据,估计了全球185个国家中36个国家的最新发病率、死亡率和癌症发展趋势。根据最新的估计数据,2020年全球新发癌症病例1929万例,其中男性1006万例,女性923万例;到2020年,全世界将有996万人死于癌症,包括553万男性和443万女性。每年有这么多人死于癌症,其中一个重要原因就是癌症没有得到及时的诊断和治疗。
18F-FDG作为反映肿瘤组织葡萄糖代谢的分子探针,早在1969年就被合成。目前,18F-FDG是最流行的基于糖代谢的放射性药物,因其显著的显像效果而被称为“世纪分子”。18F-FDG PET/CT显像对癌症患者的诊断、分期、疗效监测和预后评估具有重要价值。然而,F-18核素的生产需要正电子回旋加速器和先进的屏蔽场,成本和初期投资巨大,可达数百万美元。
然而用Ga-68标记PET探针的生产非常简单,只需要一个简单的热室。作为正电子核素,其优异的核素特性使其非常适合PET成像(89%β+),特别是对于生物半衰期较短的靶分子(T1/2为67.6min)。Ga-68具有许多优点,如良好的物理化学性质、商用的发生器、强大的化学标记多样性等。Ga-68的另一个显著优点是,在放射性药物的研究和开发中,它可以被治疗性核素(如Lu-177)所替代,因此可以将成像探针转变为放射治疗探针,实现诊断和治疗的一体化。许多文献对此进行了详细的描述,这有力地激励了研究人员开发标记Ga-68的新放射性药物。通过比较临床试验的数量也可以看出Ga-68的重要性和流行性。临床研究中Ga-68标记分子探针的数量明显高于其他核素。
2018年,曾文斌和他的同事详细介绍了各种金属核素标记的葡萄糖代谢分子。部分分子探针的成像效果甚至优于18F-FDG,且进入早期临床试验阶段。从各个方面来看,认为Ga-68是一种非常适合标记分子探针的核素。原因之一是Ga-68是正电子核素,PET的分辨率高于SPECT;另一个原因是用于制备Ga-68的68Ge-68Ga发电机的使用寿命长达一年。如果能将Ga-68标记分子探针PET肿瘤显像应用于贫困或病人数目较少的地区,将有利于那些危重病人和不适合长途转诊的肿瘤病人。
2012年,杨志和他的同事用Ga-68标记DOTA-ADG。在微波反应器中,纯化后可获得纯度大于98%的68Ga-DOTA-ADG,标记效率为85%。采用A431细胞(人皮肤鳞状细胞癌)动物模型,对68Ga-DOTA-ADG进行生物学评价,肿瘤摄取率高。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种肿瘤PET显像剂68Ga-NOTA-ADG及其制备方法和应用。
本发明的目的可以通过以下技术方案来实现:
发明人了解到,与DOTA相比,NOTA是一种更适合标记Ga-68的螯合剂,因为Ga-68的离子半径较小,68Ga-NOTA的热力学稳定常数比68Ga-DOTA高出约10个数量级。因此,本申请尝试合成NOTA-ADG并研究其生物学行为,具体方案如下:
一种肿瘤PET显像剂68Ga-NOTA-ADG,该显像剂的结构式如下:
一种如上所述肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,该方法为:在NaOAc溶液中添加前体NOTA-Amino-DG溶液,再向该溶液中添加68GaCl3,反应混合物经室温静置数分钟后,得到肿瘤PET显像剂68Ga-NOTA-ADG。
进一步地,所述的前体NOTA-Amino-DG溶液和68GaCl3的比为50μl:(0.70-0.74)GBq。
进一步地,所述培养的pH=5-6,时间为4-8min。产物不需进一步纯化,放化纯度大于95%。
进一步地,所述前体
2,2',2”-(2-(4-(3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)thioureido)benzyl)-1,4,7-triazonane-1,4,7-triyl)triacetic acid(命名为NOTA-Amino-DG)的结构式如下:
进一步地,所述前体NOTA-Amino-DG的制备方法为:向2-氨基-2-脱氧-D-葡萄糖和HEPES钠盐溶液中添加p-SCN-Bn-NOTA·3HCl,该混合溶液经培养后得到前体NOTA-Amino-DG溶液,并在-20℃下储存待用。该制备方法为常规有机合成反应,产物不需经HPLC纯化。
进一步地,所述的2-氨基-2-脱氧-D-葡萄糖和p-SCN-Bn-NOTA·3HCl的摩尔比为(40-50):(10-12)。
进一步地,所述培养的pH=8-10,时间为9-12h。
一种如上所述肿瘤PET显像剂68Ga-NOTA-ADG的应用。
进一步地,该显像剂可作为靶向肿瘤的正电子示踪剂,应用于动物模型肿瘤的显像。
与现有技术相比,本发明具有以下优点:
(1)本发明的前体第一次用于68Ga-NOTA-ADG的标记,结果显示该制备方法放射化学产率接近100%,本发明的正电子显像剂68Ga-NOTA-ADG能够作为靶向肿瘤的PET显像探针,使得68Ga-NOTA-ADG成为肿瘤的PET候选显像探针,本发明首次进行了68Ga-NOTA-ADG放射性化学合成,制备方法简单快捷,为68Ga-NOTA-ADG的科学研究和临床应用奠定了基础;
(2)在目标PET探针68Ga-NOTA-ADG的制备方法中,其选用NaOAc溶液作为反应溶剂,68GaCl3淋洗液选用0.05M HCl得到较高的标记率,标记步骤简便,放化纯度大于95%,总的放化产率将近100%(衰减校正)。此制备方法合成路线简便,合成时间短,放化纯度高,比活度满足要求。
附图说明
图1为68Ga-NOTA-ADG在ICR小鼠体内的生物分布;
图2为ICR小鼠PET显像图;
图3为肿瘤模型小鼠68Ga-NOTA-ADG PET显像。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1
前体NOTA-Amino-DG的合成:
在室温下向2-氨基-2-脱氧-D-葡萄糖(10mg,46.4μmol,4.3当量)和HEPES钠盐(30mg,115μmol)的溶液(1mL)中添加p-SCN-Bn-NOTA·3HCl(6mg,10.7μmol,1.0当量)。该溶液在室温下培养10小时,然后在-20℃下储存以供使用,反应式如下:
目标化合物PET探针68Ga-NOTA-ADG的合成:
在NaOAc溶液(0.25M,950μl)中添加50μl前体溶液。向该溶液中添加68GaCl3(淋洗液0.05M HCl,0.70-0.74GBq,4mL)。即将前体溶解在乙酸钠溶液中后,用0.05M HCl去淋洗Ge/Ga发生器,淋洗液直接加入至盛有前体的乙酸钠溶液无菌瓶中。
反应混合物在室温下培养5分钟。产物不需进一步纯化,放化纯度大于95%,反应式如下:
应用例1:68Ga-NOTA-ADG的体外稳定性实验:
以实施例1所得的68Ga-NOTA-ADG约1mCi分别置于100μL 0.9%生理盐水中,充分混匀后37℃下存放。分别在0.5h、1h、2h、3h取样,在分析型HPLC上检验其纯度变化。HPLC结果表明此PET探针3h后纯度与标记刚完成结果相同,说明分子探针非常稳定,几乎没有分解。
应用例2:68Ga-NOTA-ADG的生物分布实验:
以实施例1所得的68Ga-NOTA-ADG约100μCi尾静脉注射进8周雄性裸鼠9只,麻醉状态下,采取摘取眼球取血方式,分别在15、30和60min时各处死3只裸鼠,收集包括血、心、肺、肝、胃、大肠、脾、肾、肌肉、骨和脑组织进行称量及放射性计数。进行衰变校正后,将各个组织样品的计数与标准计数比较,结果表示为%ID/g(每克样品组织的放射性占注射剂量的百分含量),即为各个脏器对68Ga-NOTA-ADG的相对吸收值,具体如图1所示。
应用例3:68Ga-NOTA-ADG的动态活体显像试验:
以实施例1所得的68Ga-NOTA-ADG约200μCi/只通过尾静脉注射入8周雄性ICR鼠为A组,18F-FDG约100μCi/只通过尾静脉注射入8周雄性ICR鼠为B组。
结果图2,为ICR小鼠68Ga-NOTA-ADG PET显像(A)和18F-FDG PET显像(B),发现在正常ICR小鼠PET/CT图像中,显像剂68Ga-NOTA-ADG可浓集于肾脏和尿液中(图2中A);显像剂18F-FDG则主要浓集于心脏和大脑中(图2中B)。
应用例4:68Ga-NOTA-ADG的动态活体显像试验:
以实施例1所得的68Ga-NOTA-ADG约200μCi/只通过尾静脉注射入4组8周雄性肿瘤模型鼠(图3中,A为胃癌肿瘤模型,C为肝癌肿瘤模型,E为结肠癌肿瘤模型,G为肺癌肿瘤模型),18F-FDG约100μCi/只通过尾静脉注射入4组8周雄性肿瘤模型鼠(图3中,B为胃癌肿瘤模型,D为肝癌肿瘤模型,F为结肠癌肿瘤模型,H为肺癌肿瘤模型)。
注射68Ga-NOTA-ADG或18F-FDG(18F-FDG组需提前禁食2h)30min后在持续麻醉状态下进行PET/CT显像15min。
如图3,其中AB为胃癌肿瘤模型小鼠,CD为肝癌肿瘤模型小鼠,EF为结肠癌肿瘤模型小鼠,GH为肺癌肿瘤模型小鼠。A,C,E,G为68Ga-NOTA-ADG PET显像;B,D,F,H为18F-FDGPET显像。A,C,E,G组肿瘤模型小鼠中,除了肾脏和尿液中,显像剂还在肿瘤组织中摄取明显。这些结果说明68Ga-NOTA-ADG作为靶向肿瘤的PET显像探针是有效的。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (8)
1.一种肿瘤PET显像剂68Ga-NOTA-ADG,其特征在于,该显像剂的结构式如下:
2.一种如权利要求1所述肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,该方法为:在NaOAc溶液中添加前体NOTA-Amino-DG溶液,再向该溶液中添加68GaCl3,反应混合物经培养后,得到肿瘤PET显像剂68Ga-NOTA-ADG;
所述前体NOTA-Amino-DG的结构式如下:
3.根据权利要求2所述的一种肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,所述的前体NOTA-Amino-DG溶液和68GaCl3的比为50μl:(0.70-0.74)GBq。
4.根据权利要求2所述的一种肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,所述培养的pH=5-6,时间为4-8min。
5.根据权利要求2所述的一种肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,所述前体NOTA-Amino-DG的制备方法为:向2-氨基-2-脱氧-D-葡萄糖和HEPES钠盐溶液中添加p-SCN-Bn-NOTA·3HCl,该混合溶液经培养后得到前体NOTA-Amino-DG溶液,并储存待用。
6.根据权利要求5所述的一种肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,所述的2-氨基-2-脱氧-D-葡萄糖和p-SCN-Bn-NOTA·3HCl的摩尔比为(40-50):(10-12)。
7.根据权利要求5所述的一种肿瘤PET显像剂68Ga-NOTA-ADG的制备方法,其特征在于,所述培养的pH=8-10,时间为9-12h。
8.一种如权利要求1所述肿瘤PET显像剂68Ga-NOTA-ADG作为非疾病诊断的应用,该显像剂可作为靶向肿瘤的正电子示踪剂,应用于动物模型肿瘤的显像。
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