CN116082110B - 一种11c标记靶向间变性淋巴瘤激酶alk突变分子探针及应用 - Google Patents
一种11c标记靶向间变性淋巴瘤激酶alk突变分子探针及应用 Download PDFInfo
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Abstract
本发明属于核医学显像剂领域,涉及一种11C标记靶向间变性淋巴瘤激酶ALK突变分子探针及应用。本发明提供的靶向ALK突变筛查核素分子探针11C‑X‑376,其结构式如式I所示,可通过11C模块自动化装置在较短的时间内快速标记制得高核素标记率和放射化学纯度的产品。所制得的核素标记诊断试剂11C‑X‑376在非小细胞肺癌EML4‑ALK阳性H3122细胞具有特异性摄取,对于非小细胞肺癌EML4‑ALK阳性患者的临床筛查,指导用药方面具有重要价值。
Description
技术领域
本发明属于核医学显像剂领域,具体地,涉及一种11C标记靶向间变性淋巴瘤激酶ALK突变分子探针及应用。
背景技术
肺癌在全世界的发病率及死亡率一直高居榜首,根据2020年发布的全球癌症报告数据显示,全球癌症新发1929万,肺癌新发病例占11.4%;全球死亡病例996万例,其中死亡率最高的是肺癌,达到180万例。肺癌患者中超过五分之四的患者属于非小细胞肺癌(non-small cell lung cancer,NSCLC)组织类型。除了早期手术切除、常规放化疗外,随着各种药物临床试验的发展,包括靶向治疗、免疫治疗以及抗血管生成治疗的癌症其他主流治疗方法发展的越来越完善,近十余年,越来越多与肺癌发生发展相关的驱动基因被发现,而针对不同驱动基因的分子靶向治疗也彻底改变了NSCLC的治疗模式,并为患者带来显著的生存获益。NSCLC是一种高度异质性的肿瘤,不同亚型常常伴有不同的基因异常,靶向治疗通常针对某个特定的靶点,因此在治疗前了解不同患者的基因、细胞水平或分子水平差异,从而判断筛选特定基因突变的NSCLC患者具有重要的临床应用价值。
间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因作为NSCLC的驱动基因,约占其5%左右。该融合基因的形成需要ALK基因和其他基因发生断裂重排,其中与棘皮动物微管相关类蛋白4(Ecliinodemi microtubule associated protein-like 4,EML4)基因融合是最常见的(90%)。在ALK阳性晚期NSCLC的治疗方面,酪氨酸激酶抑制剂(Tyrosine kinase inhibitors,TKI)在靶向治疗方面具有重要临床价值,其中一代ALK-TKI克唑替尼在NSCLC患者临床1、II期实验中的应答率达到60%,患者的总生存率和药物应答率都远远高于传统化疗治疗,但是后期随着不同位点的基因突变会普遍发生耐药性的问题。目前针对ALK融合基因监测常用的方法包括,荧光原位杂交(Fluorescence in situhybridization,FISH),针对融合蛋白表达的免疫组织化学(immunohistochemistry,IHC)和基于聚合酶链反应(Polymerase Chain Reaction,PCR)扩增技术,这些监测方法都依赖于组织活检,存在取样有创性、分析样本不足、可重复性差等不足,且以上检查不能得到关于肿瘤形态结构如肿瘤大小、形态、位置以及肿瘤与邻近组织器官额毗邻关系等重要信息。而利用靶向放射性药物通过核医学PET/CT诊断具有在体、动态、无创、监测灵敏度高、准确率高等优点,已在临床得到广泛应用。
发明内容
为了实现非小细胞肺癌EML4-ALK基因突变患者的在体精准无创筛选,实现精准给药,并克服现有筛查技术有创、准确率低的不足:本发明提供了一种11C标记靶向ALK突变分子探针、前体、制备方法及应用,该核医学分子探针可被EML4-ALK阳性非小细胞肺癌细胞特异摄取,灵敏度高,结果准确。
本发明提供一种11C标记靶向间变性淋巴瘤激酶ALK突变分子探针11C-X-376,其结构式如式I所示:
根据本发明,所述探针的11C标记前体的结构式如式II所示:
本发明所述探针的11C标记前体的制备方法可包括如下步骤:
以(R)-1-(2,6-二氯-3-氟苯基)乙醇和3-氨基-4-溴-6-氯哒嗪作为起始原料,经过亲核取代、氨基BOC保护、CO插羰、酯水解、缩合、脱保护,合成得到哒嗪环氨基BOC保护的所述探针的11C标记前体(11C-X-376标记前体化合物12)。
所述探针的制备方法可包括如下步骤:
回旋加速器轰击产生11C-CO2,经还原,转化得到[11C]CH3OTf,其作为探针标记用甲基化试剂;一定量标记前体通过自动化合成装置以NaOH做碱,DMSO做溶剂,加热条件下自动化标记,经脱保护、中和,C18制备纯化得到所述探针。
优选地,所述自动化标记的时间为4-10min。
优选地,所述脱保护采用0.8-1.2N HCl在90-110℃下进行。
优选地,加入NaOH进行所述中和。
本发明还提供上述分子探针在制备非小细胞肺癌间变性淋巴瘤激酶ALK突变核医学检测试剂中的应用。
其中所述非小细胞肺癌优选为EML4-ALK阳性非小细胞肺癌。
所述核医学试剂的类型包括但不限于癌症检测筛查试剂、预后判断试剂或疗效评价试剂。
本发明提供一种靶向ALK突变筛查11C标记分子探针,可通过11C模块自动化装置在较短的时间内快速标记制得高核素标记率和放射化学纯度的11C-X-376。所制得的核素标记诊断试剂11C-X-376在非小细胞肺癌EML4-ALK阳性H3122细胞具有特异性摄取。本发明构建得到的放射性诊断试剂11C-X-376对于临床NSCLC患者EML4-ALK基因突变的患者筛选,指导用药具有一定的研究意义及临床应用价值。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
附图说明
通过结合附图对本发明示例性实施方式进行更详细的描述,本发明的上述以及其它目的、特征和优势将变得更加明显。
图1-1示出了11C-X-376标记前体12的合成路线。
图1-2示出了11C-X-376标记前体12的质谱图。
图2示出了11C-X-376标记流程图。
图3示出了11C-X-376质控结果图。
图4示出了11C-X-376在EML4-ALK突变阳性H3122细胞摄取结果图。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式,然而应该理解,可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
实施例中未注明具体条件者,皆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。
实施例1
11C-X-376标记前体化合物12的制备,路线如图1-1所示。
(1)化合物3的合成
在100mL茄形瓶中,将化合物1(200mg,0.96mmol)溶于无水THF(20mL),冰浴搅拌下缓慢加入60% NaH(42mg,1.05mmol),反应液移到油浴加热至60℃搅拌20分钟,将化合物2(199mg,0.96mmol)加入到反应液,60℃反应7小时。减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为乙酸乙酯:石油醚=0%到30%(v/v),得到化合物3(150mg,产率47%),淡黄色固体。LRMS calcd.For C12H9Cl3FN3O[M+H]+335.9873,337.9844.Found.377.3,379.3.
(2)化合物4的合成
在100mL茄形瓶中,将化合物3(150mg,0.45mmol)溶于无水DCM(20mL),依次加入三乙胺(226mg,2.23mmol),DMAP(11mg,0.09mmol)和(Boc)2O(195mg,0.89mmol)室温搅拌反应40小时,减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为乙酸乙酯:石油醚=0%到20%(v/v),得到化合物4(145mg,产率60%),淡黄色固体。LRMS calcd.For C22H25Cl3FN3O5[M+H]+536.0922,538.0983.Found.537.0,539.1.
(3)化合物5的合成
在100mL茄形瓶中,将化合物4(145mg,0.27mmol),醋酸钠(44mg,0.54mmol),Pd(dppf)Cl2CH2Cl2(22mg,0.03mmol)溶于DMF(10mL)和乙醇(7mL)的混合溶剂中,在一氧化碳的条件下90℃搅拌反应10小时。减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为乙酸乙酯:石油醚=0%到50%(v/v),得到化合物5(101mg,产率65%),淡黄色固体。LRMScalcd.For C25H30Cl2FN3O7[M+H]+574.1523,576.1494.Found.574.2,576.0.
(4)化合物10的合成
在100mL茄形瓶中,将化合物5(100mg,0.17mmol)溶于四氢呋喃(10mL),加入1N氢氧化锂水溶液(0.26mL,0.26mmol),常温搅拌48小时,减压除去溶剂,加入水(6mL),1N盐酸调pH=5,乙酸乙酯(15mL×3)萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压除去溶剂,得到化合物10(60mg,产率53%),淡黄色固体。LRMS calcd.For C23H26Cl2FN3O7[M+H]+546.1210,548.1181.Found.546.0,548.1.
(5)化合物8的合成
在100mL茄形瓶中,将化合物6(1g,4.22mmol),DIPEA(1.63g,12.66mmol)和HATU(1.93g,5.06mmol)溶于DMF(25mL),室温搅拌20分钟,将化合物7(970mg,4.43mmol)加入到反应液室温搅拌5小时,减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为乙酸乙酯:石油醚=0%到40%(v/v),得到化合物8(1.11g,产率60%),淡黄色固体。LRMS calcd.ForC24H29N3O5[M+H]+440.2185.Found.440.2.
(6)化合物9的合成
在100mL茄形瓶中,将化合物8(1.1g,2.51mmol)溶于三氟乙酸(20mL)室温搅拌6小时,当反应结束,减压除去溶剂,得到化合物9(722mg,产率85%),淡黄色固体。LRMScalcd.For C19H21N3O3[M+H]+340.1661.Found.340.4.
(7)化合物11的合成
在100mL茄形瓶中,将化合物10(60mg,0.11mmol),DIPEA(57mg,0.44mmol)和HATU(59mg,0.15mmol)溶于DMF(7mL),室温搅拌20分钟,将化合物9(45mg,0.13mmol)加入到反应液室温搅拌5小时,减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为甲醇:二氯甲烷=0%到10%(v/v),得到化合物11(33mg,产率35%)。LRMS calcd.For C42H45Cl2FN6O9[M+H]+867.2687.Found.867.3
(8)化合物12(标记前体)的合成
在100mL茄形瓶中,将化合物11(33mg,0.04mmol)溶于乙醇(10mL),加入10%Pd/C(3.3mg),氢气下室温搅拌6小时,经硅藻土过滤,分别用乙醇(10mL)和二氯甲烷(10mL)洗涤,滤液减压除去溶剂,残余物经快速纯化色谱仪纯化,流动相为甲醇:二氯甲烷=0%到10%(v/v),得到化合物12(12mg,产率43%)。LRMS calcd.For C34H39Cl2FN6O7[M+H]+733.2320.Found.733.4.质谱图如图1-2所示。
实施例2
11C-X-376的放射性核素标记,流程图如图2所示。
将0.5-1mg前体溶于0.5mL DMSO中,加入10μL 1N NaOH溶液,混合物溶液于110℃条件下捕获[11C]CH3OTf标记反应5min,经1mL 1N HCl,100℃脱保护180s,1mL 1M NaOH中和,经C18反向制备纯化,溶液蒸干,重新溶于磷酸缓冲液中(0.1mol/L,pH 7.4),过除菌滤膜即得放化产率(RCY>20%,n=3)(未经衰减校正),放化纯度(RCP>92%,n=3)的11C-X-376。
实施例3
11C-X-376的质控
使用Radio-HPLC对产物进行质量检测,11C-X376通过C18柱的纯化,放化纯度可达到90%以上。如图3所示,在0.1%甲酸水/乙腈梯度洗脱,波长为254nm的条件下,使用Eclipse Plus C18(150um)色谱柱,放射产物出峰时间为8.9min,与冷化合物出峰时间一致,说明11C标记产物正确。
实施例4
11C-X-376在EML4-ALK突变阳性H3122细胞摄取实验
将H3122用含有10%FBS和1%双抗的1640培养基在75cm2的培养瓶中培养,将培养瓶置于37℃,含5% CO2的培养箱中。采用胰酶将处于对数生长期的H3122细胞进行消化,采用0.25%的胰酶消化2-3min,镜下观察细胞形状变圆,则将胰酶移去以停止消化。加入培养液吹打细胞并收集至离心管中离心(1000r/min×3min)。移去上清液,加入相应的培养基吹打均匀,对细胞进行计数,取10μL吹打均匀的细胞加至细胞计数板,测定细胞悬液中单位体积细胞数量,并配制成2×105cells/mL。
取1mL细胞加至24孔板中,静置于37℃,5% CO2培养箱中孵育24h。实验开始后,将24孔板中细胞培养液移去,并使用PBS洗涤(2×1mL)。将11C-X-376使用培养液配制(1μCi/mL)。每孔中加入1mL的分子探针,轻微摇匀后将24孔板静置于37℃孵育箱中。5min、15min、30min后,将24孔培养板取出,将培养液移除,加入冷PBS洗涤(3×1mL),再加入0.2mL1.0mol/L NaOH消化,5-10min后将细胞裂解液转移至γ-counter管中,测定计数。取100μL配制好的探针溶液,加入到计数管中作为参考,与消化的细胞液同时测定计数。实验结果表示为:%uptake/106cells。
结果如图4所示,H3122细胞对于探针的摄取随时间增加而升高。在5分钟时,H3122细胞的摄取值为2.58±0.13,15分钟时,H3122摄取值达到5.15±0.29。在30分钟时,H3122细胞的摄取值最高,达到7.60±0.36,说明11C-X-376在EML4-ALK阳性H3122细胞中有较高摄取,且随时间延长摄取增加。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (10)
1.一种11C标记靶向间变性淋巴瘤激酶ALK突变分子探针,其结构式如式I所示:
2.根据权利要求1所述的分子探针,其中,所述探针的11C标记前体的结构式如式II所示:
3.根据权利要求2所述的分子探针,其中,所述探针的11C标记前体的制备方法如下:
以(R)-1-(2,6-二氯-3-氟苯基)乙醇和3-氨基-4-溴-6-氯哒嗪作为起始原料,经过亲核取代、氨基BOC保护、CO插羰、酯水解、缩合、脱保护,合成得到哒嗪环氨基BOC保护的所述探针的11C标记前体。
4.根据权利要求3所述的分子探针,其中,所述探针的制备方法如下:
回旋加速器轰击产生11C-CO2,经还原,转化得到[11C]CH3OTf,其作为探针标记用甲基化试剂;一定量标记前体通过自动化合成装置以NaOH做碱,DMSO做溶剂,加热条件下自动化标记,经脱保护、中和,C18制备纯化得到所述探针。
5.根据权利要求4所述的分子探针,其中,所述自动化标记的时间为4-10min。
6.根据权利要求4所述的分子探针,其中,所述脱保护采用0.8-1.2NHCl在90-110℃下进行。
7.根据权利要求4所述的分子探针,其中,加入NaOH进行所述中和。
8.权利要求1-7中任意一项所述的分子探针在制备非小细胞肺癌间变性淋巴瘤激酶ALK突变核医学检测试剂中的应用。
9.根据权利要求8所述的应用,其中,所述非小细胞肺癌为EML4-ALK阳性非小细胞肺癌。
10.根据权利要求8所述的应用,其中,所述核医学检测试剂为癌症检测筛查试剂、预后判断试剂或疗效评价试剂。
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