CN113651662A - 一种靶向fgfr的新型肿瘤pet分子探针及其制备方法 - Google Patents
一种靶向fgfr的新型肿瘤pet分子探针及其制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种核医学技术领域,具体涉及一种靶向FGFR的新型肿瘤PET分子探针及其制备方法。
背景技术
FGFR(fibroblast growth factor receptor)酪氨酸激酶家族包括FGFR1、FGFR2、FGFR3和FGFR4。成纤维细胞生长因子相关信号异常是许多癌症的驱动因素,近年来FGFR抑制剂的研究取得很大成功,2019年首个FGFR泛抑制剂Erdafitinib被FDA批准上市,目前FGFRs抑制剂的研究则集中于实现亚型的高选择性。在生理状态下,FGFR4信号通路被严格控制,而FGFR4信号失调导致癌症的发生发展、增殖、存活及转移。
39%的食管鳞状细胞癌患者和82%的恶性外周神经鞘膜瘤患者存在FGFR4异常过表达,伴随着不良预后和短的生存期。在乳腺癌患者中大约有32%FGFR4的mRNA表达水平上升。此外,FGFR4过表达的星形胶质细胞瘤、肝癌、卵巢癌、胃癌、胰腺癌、结肠癌有较高的侵袭性,预示着癌症晚期和短的生存期,而抑制FGFR4信号通路能显著降低其侵袭性,表明FGFR4是潜在的治疗靶标。
不同肿瘤中,FGFR4信号异常主要有以下三点:(1)FGFR4基因扩增或过转录所致FGFR4过表达;(2)FGFR4突变导致其活性持续激活;(3)癌细胞或者基质细胞中FGFR4的配体表达上调,导致其通过自分泌或旁分泌途径过度活化FGFR4信号通路。
但是目前尚无特异性FGFR靶点特异性核医学示踪剂。
PET全称为正电子发射计算机断层显像(positron emission tomography PET),是反映病变的基因、分子、代谢及功能状态的显像设备。它是利用正电子核素标记葡萄糖等人体代谢物作为显像剂,通过病灶对显像剂的摄取来反映其代谢变化,从而为临床提供疾病的生物代谢信息。是当今生命科学、医学影像技术发展的新里程碑。CT全称为电子计算机X射线断层扫描技术(Computed Tomography),它是利用X射线对人体进行体层检查。PET/CT显像剂为将PET和CT有机的结合在一起,使用同一个检查床合用一个图像工作站,PET/CT同时具有PET、CT及将PET图像与CT图像融合等功能。
目前临床上尚未有针对FGFR(fibroblast growth factorreceptor)酪氨酸激酶特异性PET探针上市应用。
发明内容
本发明是为了解决上述问题而进行的,目的在于提供一种靶向FGFR的新型肿瘤PET分子探针及其制备方法。
本发明提供了一种靶向FGFR的新型肿瘤PET分子探针,具有这样的特征,结构式如下:
在本发明提供的靶向FGFR的新型肿瘤PET分子探针中,还具有这样的特征,合成反应方程式如下:
,其中,K222为氨基聚醚。
本发明提供了一种靶向FGFR的新型肿瘤PET分子探针的制备方法,用于制备上述靶向FGFR的新型肿瘤PET分子探针,具有这样的特征,合成步骤包括:步骤1,用惰性气体A将含有18F离子的靶水加压,传出后,通过QMA柱,将18F离子吸附在QMA柱上,加入碳酸钾和氨基聚醚,将QMA柱吸附的18F离子冲入反应管内,90-110℃、惰性气体B下蒸发溶液至干后,再加入无水有机溶剂CAN形成共沸溶液,在90-110℃下继续蒸发至干,进入步骤2;步骤2,用DMSO/CAN溶解PET分子探针前体,加入反应管,一定温度反应一定时间,纯化,即得PET分子探针。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,惰性气体A为氩气。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,惰性气体B为氮气。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,步骤2中的一定温度为80-110℃。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,步骤2中的一定时间为10-20分钟。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,步骤1中,碳酸钾和氨基聚醚的质量比3:(12-15)。
在本发明提供的靶向FGFR的新型肿瘤PET分子探针的制备方法中,还具有这样的特征:其中,步骤1中,DMSO与CAN的体积比为1:(4-6)。
发明的作用与效果
根据本发明所涉及的一种靶向FGFR的新型肿瘤PET分子探针,结构式如下:
通过18F离子进行标记,亲核取代,纯化后即得PET分子探针。因为本发明提供的靶向FGFR的新型肿瘤PET分子探针制备方法简单,原料来源广泛,制备得到的PET分子探针对FGFR(酪氨酸激酶)具有特异性,并且对肿瘤具有高的靶向性摄取,所以本发明提供的靶向FGFR的新型肿瘤PET分子探针可以作为针对FGFR(酪氨酸激酶)特异性的PET探针。
附图说明
图1是本发明的实施例2中标准品的紫外谱图;
图2是本发明的实施例2中PET分子探针的放射性谱图;以及
图3为本发明的实施例4中Micro-PET的扫描结果图。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,以下结合实施例及附图对本发明作具体阐述。
<实施例1>
一种靶向FGFR的新型肿瘤PET分子探针的制备反应式如下:
其中,K222为氨基聚醚。
靶向FGFR的新型肿瘤PET分子探针的合成步骤如下:
步骤1,用氩气加压含有18F离子的靶水,传出后,将18F离子吸附在QMA柱上,将碳酸钾和氨基聚醚按照质量比3:13,并将碳酸钾溶解在1mL水中,氨基聚醚溶解在9mL乙腈中,两者混合得复合溶液,取K2CO3/KryptofixTM 2.2.2.(氨基聚醚)的复合溶液1.5mL,将QMA柱吸附的18F离子冲入1#反应管内,在100℃、氮气流下蒸发溶液至干,然后加入2mL无水乙腈形成共沸溶液,在100℃下继续蒸发至干,进入步骤2;
第2步.亲核取代:1#反应管蒸发至干后,在2#反应管中加入2mg PET分子探针前体并用1mL DMSO/CAN(体积比为1:5)溶解并转移至1#反应管中,在120℃进行亲核取代反应15min,反应结束后,得反应液;
第3步,纯化处理:在反应液中加入注射用水,经过Sep-Pak tC18萃取小柱(水洗掉游离18F离子、KryptofixTM 2.2.2.及极性分子等),然后用乙醇洗脱得到粗产品;
第4步,半制备产物:用半制备型高效液相色谱(semi-preparative high-performance liquid chromatography)纯化,反相C-18半制备色谱柱,40%乙醇水为流动相,收集目标产物然后进行蒸发浓缩,然后用含10%乙醇的生理盐水溶解,并加入抗坏血酸(2mg,0.03mmol)(防止辐射自分解),再通过无菌滤膜将PET分子探针收集于无菌瓶中。
<实施例2>
靶向FGFR的新型肿瘤PET分子探针及标准品的HPLC的质量控制方法
HPLC的分离条件:YMC C-18反相色谱柱,300mm*4.6mm,流动相A为水,流动相B为乙腈,梯度洗脱方法如下:
PET分子探针的质量检测结果如表1。
表1 PET分子探针的质量检测结果
性状 | 澄清液体 |
pH值 | 7.0 |
放射性化学纯度 | 放射性化学纯度大于98% |
放射性比活度 | 放射性浓度大于20mCi/ml |
PET分子探针及标准品的HPLC质控结果如图1-2所示。
根据图1-2可知,标准品的紫外峰的保留时间为14.813min,PET分子探针的放射性峰的保留时间为14.866min,通过对PET分子探针的放射性谱图峰面积积分,获得其放射性化学纯度为98.87%
<实施例3>
体外稳定性实验
实验方法:将PET分子探针在室温下放置,分别在多个时间内采用TLC法测其放化纯度,观察其稳定性。
实验结果:质量控制中测定的放射性化学纯度为1-6h的数据
<实施例4>
荷瘤鼠模型PET扫描显像
1.1小鼠给药
每只小鼠给药前称重,经尾静脉单次注射PET分子探针(100±20uCi),记录初始注射剂量、测初始注射剂量时间、注射时间、残留剂量、测残留剂量时间,通过Micro PET扫描技术考察给药后不同时间点各受试物在荷瘤鼠体内的组织分布特征。
1.2Micro-PET扫描
在给药的第30min、1h、2h和第3h进行Micro-PET扫描。扫描前将每只小鼠称重并记录,用异氟烷麻醉剂进行预麻醉,将小鼠固定在扫描床上,记录小鼠床上摆位,开始Micro-PET扫描。每个床位10min;扫描能窗:350-650Kev,记录好注射剂量,时间,测残留剂量,测残留时间。
Micro-PET扫描完成后,数据形成文件夹等扫描信息,扫描完成后对原始数据进行重建,重建完成后用图像处理软件PMOD进行图像及数据处理,勾画脑、心、肝、肾、骨(骨关节)、肌肉等脏器为感兴趣区域,勾画完成后获得单位体积感兴趣区域的放射性活度值,并计算获得各脏器的%ID/g数值。
图3为本实施例4的Micro-PET扫描结果图。
如图3所示,PET分子探针在肿瘤有高的靶向性摄取,肿瘤对探针的摄取值随时间延长增加。
实施例的作用与效果
根据本实施例所涉及的一种靶向FGFR的新型肿瘤PET分子探针,结构式如下:
通过18F离子进行标记,亲核取代,纯化后即得PET分子探针。因为本实施例提供的靶向FGFR的新型肿瘤PET分子探针制备方法简单,原料来源广泛,对FGFR(酪氨酸激酶)具有特异性,同时PET分子探针对肿瘤具有高的靶向性摄取,所以本实施例提供的靶向FGFR的新型肿瘤PET分子探针可以作为针对FGFR(酪氨酸激酶)特异性的PET探针。
上述实施方式为本发明的优选案例,并不用来限制本发明的保护范围。
Claims (9)
3.一种靶向FGFR的新型肿瘤PET分子探针的制备方法,用于制备权利要求1或2所述的靶向FGFR的新型肿瘤PET分子探针,其特征在于,合成步骤包括:
步骤1,用惰性气体A将含有18F离子的靶水加压,传出后,通过QMA柱,将所述18F离子吸附在所述QMA柱上,加入碳酸钾/氨基聚醚,将QMA柱吸附的18F冲入反应管内,在90-110℃、惰性气体B下蒸发溶液至干后,再加入无水有机溶剂CAN形成共沸溶液,在90-110℃下继续蒸发至干,进入步骤2;
步骤2,用DMSO/CAN溶解PET分子探针前体,加入所述反应管,一定温度反应一定时间,纯化,即得所述PET分子探针。
4.根据权利要求3所述的靶向FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,所述惰性气体A为氩气。
5.根据权利要求3所述的靶向FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,所述惰性气体B为氮气。
6.根据权利要求3所述的靶向FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,步骤2中的一定温度为80-100℃。
7.根据权利要求3所述的靶向FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,步骤2中的一定时间为10-20分钟。
8.根据权利要求3所述的FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,步骤1中,所述碳酸钾和所述氨基聚醚的质量比为3:(12-15)。
9.根据权利要求3所述的FGFR的新型肿瘤PET分子探针的制备方法,其特征在于:
其中,步骤1中,所述DMSO与所述CAN的体积比为1:(4-6)。
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