CN113521320A - 一种靶向trem2受体的pet显像剂及其制备方法与应用 - Google Patents
一种靶向trem2受体的pet显像剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种靶向TREM2受体的PET显像剂68Ga‑NOTA‑COG1410及其配体化合物。本发明还公开了其制备方法,以及其在鉴别验证和肿瘤方面的应用。本发明的靶向TREM2受体的PET显像剂及其配体化合物化学结构新颖,具有分子量小、代谢快、受试者受到的辐射剂量低的优点,能实现对肿瘤的分期和鉴别诊断。
Description
技术领域
本发明涉及放射性药物化学技术领域,特别是涉及一种靶向TREM2受体的PET显像剂及其制备方法与应用。
背景技术
正电子发射断层扫描(PositronEmissionTomography,PET)是目前在活体检测肿瘤和疾病发生发展的最佳影像学设备,能实现对细胞代谢和功能的高分辨率显像,从分子水平对人体的生理、生化过程进行无创、三维、动态研究。PET检查依赖于光谱性或者特异性的靶向正电子显像剂在目标器官的代谢、吸收。18F-FDG是目前PET最常用的显像剂,但是18F-FDG存在特异性较差、有时出现假阳性或假阴性、不能区分肿瘤和炎症等缺点。因此18F-FDG是一种非特异性的显像剂,关于肿瘤和炎症的鉴别诊断和研究还需要研发新型的、特异性的显像剂。
近年来,肿瘤微环境成为了研究的热点。肿瘤微环境中存在许多非肿瘤宿主细胞,例如炎性细胞,成纤维细胞和内皮细胞,它们会影响肿瘤细胞的生物学功能和耐药性。巨噬细胞是浸润的基质细胞的主要成分,被称为肿瘤相关的巨噬细胞(TAMs)。巨噬细胞主要分为M1和M2型,M1型又称经典型巨噬细胞,促炎,抗肿瘤;而M2型被称作又称替代性活化巨噬细胞,抗炎,促肿瘤。TAMs倾向于M2型巨噬细胞表型。因此,寻找靶向TAMs的高特异性、高表达量的靶点对于肿瘤的诊断、分期、鉴别诊断和治疗尤为重要。基于上述阐述,有必要寻找新型的特异性靶向分子探针或者显像策略来实现高灵敏度、高靶向性的消化系统肿瘤分子多模态成像,来诊断消化系统肿瘤及活体可视化动态监测消化系统肿瘤生物学行为变化,并用于炎症和肿瘤的鉴别诊断;并选择合适人群进行分子靶向治疗、核素治疗或多学科联合治疗,从而实现消化系统肿瘤“个体化、一体化”诊疗模式。
髓系细胞触发受体2(TREM2,triggeringreceptorexpressedonmyeloidcells 2)属于免疫球蛋白超家族的一个单程传递膜受体,最初在单核细胞来源的树突状细胞和小鼠巨噬细胞中发现。TREM2基因位于人类6p21.1染色体,小鼠17C3染色体上具有免疫功能的基因簇内,其在外周主要于髓系细胞表达,如巨噬细胞、树突状细胞、粒细胞等。随着研究的深入,研究人员发现TREM2不仅涉及参与细胞间及细胞-细胞外基质粘附、细胞信号转导及间充干细胞转化等许多生理过程,而且与肿瘤发生、转移及预后密切相关,并且TREM2的表达与巨噬细胞的极化息息相关。TREM2最早发现其在小胶质细胞高表达,大量的研究集中在TREM2相关信号通路与阿尔茨海默病的联系。近年来,免疫微环境研究进展,TREM2与肿瘤的联系逐渐受到重视。Colonna等研究发现Trem2-/-小鼠比野生型小鼠对各种癌症的生长更有抵抗力这一现象,Trem2-/-小鼠也对抗PD-1免疫疗法更有疗效,结合基因图谱和多变量生存分析,最终发现TREM2与TAMs功能相关,TREM2在M2型巨噬细胞中高表达,并且具有极强的特异性,也有学者认为TREM2是M2型巨噬细胞的标志物之一。而M1型巨噬细胞主要在炎症病灶聚集,其低表达TREM2,这与TAMs高表达TREM2形成巨大的差异。因此,以TREM2为靶点的显像进行肿瘤诊断、分期和鉴别炎症和肿瘤有理论基础。
索科普哈应用研究产品商业化公司在WO2016205941A中公开了通过在接头配体残基延伸的肽配体支架的N-末端上添加放射性金属螯合基团来靶向B1R的特异性治疗药物,但其使用的金属元素半衰期较长,人体接受的辐射剂量较高,并且在尾静脉注射后半小时尚不能清晰显像,存在图像效果不佳的问题。
ShengpanChen对多肽COG1410与TREM2靶点的关系以及COG1410与TREM2相关的治疗活性进行了报道(参见“TREM2 activation attenuatesneuroinflammation andneuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage inmice”,Chen et al.Journal of Neuroinflammation(2020)17:168),但其并未关注COG1410可用于制备以TREM2为靶点的显像剂。
原子高科股份有限公司在CN110305187A中公开了前列腺癌诊断试剂68Ga-NO TA-ANCPPSMA及其制备方法和应用,但其探针主要用于前列腺癌,存在适用范围受限的问题。
发明内容
本发明的目的在于针对现有的显像剂分子量大、代谢慢、受试者受到的辐射剂量高的问题,提供一种Ga-68标记的TREM2受体的PET显像剂及其制备方法,及其在鉴别炎症和肿瘤方面的应用。
本发明为实现上述目的采用的技术方案是如下:
一种靶向TREM2受体的PET显像剂,具体为68Ga-NOTA-COG1410,具有如式(I)所示结构:
进一步地,具体为NOTA-COG1410,具有如式(II)所示结构:
本发明还公开了如上所述的靶向TREM2受体的PET显像剂的制备方法,所述方法包括如下步骤:
1)合成NOTA-COG1410;
2)向68GaCl3溶液中先后加入NaOAc缓冲液和NOTA-COG1410,升温反应得到68Ga-NOTA-COG1410。
进一步地,反应温度为70-90℃,反应时间为5-20min。
本发明还公开了如上所述的的靶向TREM2受体的PET显像剂在个体中成像的方法,将细胞或组织与如式(I)所示的化合物接触,检测在所述细胞或组织内的该化合物以及对在所述细胞或组织内的该化合物进行成像。
进一步地,所述成像是通过正电子发射断层扫描(PET)进行的。
进一步地,所述细胞或组织为在体内或在体外的。
本发明还公开了如上所述的靶向TREM2受体的PET显像剂用于在个体中成像或诊断的用途。
进一步地,所述成像或诊断的用途为用于炎症、癌症、肿瘤或赘生物成像或诊断的用途。
进一步地,所述癌症包括眼癌、直肠癌、结肠癌、宫颈癌、前列腺癌、乳腺癌、膀胱癌、口腔癌、胃癌、肝癌、胰腺癌、肺癌、子宫癌、卵巢癌、睾丸癌、肾癌、脑癌、中枢神经系统癌、咽喉癌、皮肤黑色素瘤、急性淋巴细胞白血病、急性髓系白血病、尤因肉瘤、卡波西肉瘤、基底细胞癌和鳞状细胞癌、小细胞肺癌、绒膜癌、横纹肌肉瘤、血管肉瘤、血管内皮瘤、肾母细胞瘤、神经母细胞瘤、食道癌、喉癌、淋巴瘤、神经纤维瘤、结节性脑硬化、血管瘤或淋巴癌中的一种或几种;
再进一步地,所述癌症为具体癌症为结肠癌,所述炎症为结肠炎。
本发明的优点和效果:
1)COG1410为TREM2的配体,其由12个氨基酸组成、分子量1410而得名。由于COG1410无法直接连接放射性核素Ga-68,本发明将COG1410的一个伯氨基连接螯合剂NOTA,再标记放射性核素Ga-68,得到68Ga-NOTA-COG1410,具有半衰期更短从而使得人体受到的辐射剂量显著降低的优点;
2)68Ga-NOTA-COG1410相较于anti-TREM2 mAb的显像,68Ga-NOTA-COG1410分子量小、代谢快,受试者受到的辐射剂量更低,适合临床转化,本发明的技术方案在尾静脉注射后半小时即可清晰显像,且腹部背景较低,图像效果极佳,适用范围广,富含TAMs的肿瘤组织均可显像。
附图说明
图1为68Ga-NOTA-COG1410的紫外光谱图;
图2为68Ga-NOTA-COG1410的体外稳定性试验结果;
图3为68Ga-NOTA-COG1410的体外细胞结合实验结果;
图4为68Ga-NOTA-COG1410的血药浓度-时间曲线;
图5为68Ga-NOTA-COG1410的PET成像图。
具体实施方式
以下通过实施例,对本发明作进一步的具体说明,但这些实施例不对本发明有任何限制。
实施例1
化合物1的合成:
1)称取MBHA树脂(0.2mmol,0.77g,sub:0.26mmol/g)到固相管中,加入DMF,氮气鼓吹2小时;
2)用DMF洗涤树脂三次;
3)加入20%piperidine/DMF,氮气鼓吹0.5h;
4)用DMF洗涤树脂五次;
5)往上述树脂加入Fmoc保护的氨基酸,加入DMF溶液混匀,再依次加入缩合剂和碱,氮气鼓吹反应1h;
6)按以下氨基酸投料表,重复上述操作依次连接各氨基酸。
表1氨基酸投料表
实施例2
NOTA-COG1410的合成:
1)将化合物1树脂干燥完成后,加入切割溶液(2.5%Tis/2.5%H2O/2.5%DTT//92.5%TFA),室温下震荡5小时;
2)过滤树脂并收集滤液;
3)将上述滤液缓慢倒入冷的异丙醚溶液中,用3000转的离心机离心得到粗品肽;
4)将粗品肽用异丙醚洗涤两次,然后干燥得到50mg粗品。
粗品用反相制备HPLC纯化(Eluent of 0.1%TFA H2O/CH3CN on C-18columnchromatography),收集目标馏分,冻干得到目标化合物NOTA-COG1410(10.9mg,95.0%纯度),产品性状为白色固体。NOTA-COG1410纯化条件见表2。
表2NOTA-COG1410纯化条件
实施例3
68Ga-NOTA-COG1410的合成:
向68CaCl3溶液中先后加入0.1mol/L的NaOAc缓冲液和100μg NOTA-COG1410,80℃反应10min得到68Ga-NOTA-COG1410,谱图如图1所示。
实施例4
分子探针体内外稳定性评价体外稳定性实验:
通过将20μL 7.4MBq的68Ga-NOTA-COG1410加入10%的胎牛血清或PBS(pH=7.2)溶液中,37℃孵育后,用HPLC测定其放射化学纯度。体内稳定性实验:通过选择6周龄裸鼠20只,尾静脉注射68Ga-NOTA-COG1410后,不同时间点各断尾5只取血100μl,血液收集在肝素化离心管中,离心分离获得血浆,用RTLC测量68Ga-NOTA-COG1410和游离[68Ca]镓离子的相对含量,结果如图2所示,稳定性在NS和血清中始终高于百分之90。
实施例5
体外细胞结合实验(结果如图3所示):
将68Ga-NOTA-COG1410分别与原代巨噬细胞株进行细胞结合实验,在体外验证其与细胞结合活性。细胞结合实验分以下两步进行:
(1)受体结合细胞饱和实验:不同浓度梯度68Ga-NOTA-COG1410分别与TAMs于37℃孵育2h,然后通过预冷0.01M PBS清洗去除未结合的探针,用自动γ计数器测量相应的放射性计数,得到的放射性计数与探针浓度经GraphPadPrism软件处理得到平衡解离常数Kd以及最大结合值Bmax。
(2)受体结合细胞竞争抑制实验:TAMs培养孔内先加入固定浓度68Ga-NOTA-COG1410,再加入不同抑制倍数的非标记的NOTA-COG1410,37℃孵育2h,同样通过GraphPadPrism软件进行处理,得到半抑制常数IC50。
实施例6
体内生物分布及药代动力学实验生物分布实验:
6周龄原位消化系统肿瘤模型鼠25只,向其尾静脉注射68Ga-NOTA-COG1410,麻醉状态下处死后,采集感兴趣的脏器组织,测其所有组织样品的重量及放射性计数。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)。药代动力学实验:前面步骤同生物分布实验,分别于68Ga-NOTA-COG1410注射后不同时间点断尾,用毛细血管取约为5μL血样,置于计数管底部,测其计数,绘制其血药浓度-时间曲线(见图4)。
实施例7
肿瘤模型鼠动态活体显像试验:
68Ga-NOTA-COG1410约200μCi/只通过尾静脉注射入3组8周雄性模型鼠,在持续麻醉状态下进行PET显像。结果发现在如图5所示的PET图像中,显像剂可浓集于肿瘤组织中。
上述实施例只是为了说明本发明的技术构思及特点,其目的是在于让本领域内的普通技术人员能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰,都应涵盖在本发明的保护范围内。
Claims (10)
3.一种如权利要求1所述的靶向TREM2受体的PET显像剂的制备方法,其特征在于,所述方法包括如下步骤:
1)合成NOTA-COG1410;
2)向68GaCl3溶液中先后加入NaOAc缓冲液和NOTA-COG1410,升温反应得到68Ga-NOTA-COG1410。
4.如权利要求3所述的制备方法,其特征在于,反应温度为70-90℃,反应时间为5-20min。
5.一种使用如权利要求1所述的靶向TREM2受体的PET显像剂在个体中成像的方法,其特征在于,将细胞或组织与如式(I)所示的化合物接触,检测在所述细胞或组织内的该化合物以及对在所述细胞或组织内的该化合物进行成像。
6.如权利要求5所述的在个体中成像的方法,其特征在于,所述成像是通过正电子发射断层扫描(PET)进行的。
7.如权利要求5所述的在个体中成像的方法,其特征在于,所述细胞或组织为在体内或在体外的。
8.如权利要求1所述的靶向TREM2受体的PET显像剂用于在个体中成像或诊断的用途。
9.如权利要求8所述的用于在个体中成像或诊断的用途,其特征在于,所述成像或诊断的用途为用于炎症、癌症、肿瘤或赘生物成像或诊断的用途。
10.如权利要求9所述的用于在个体中成像或诊断的用途,其特征在于,所述癌症包括眼癌、直肠癌、结肠癌、宫颈癌、前列腺癌、乳腺癌、膀胱癌、口腔癌、胃癌、肝癌、胰腺癌、肺癌、子宫癌、卵巢癌、睾丸癌、肾癌、脑癌、中枢神经系统癌、咽喉癌、皮肤黑色素瘤、急性淋巴细胞白血病、急性髓系白血病、尤因肉瘤、卡波西肉瘤、基底细胞癌和鳞状细胞癌、小细胞肺癌、绒膜癌、横纹肌肉瘤、血管肉瘤、血管内皮瘤、肾母细胞瘤、神经母细胞瘤、食道癌、喉癌、淋巴瘤、神经纤维瘤、结节性脑硬化、血管瘤或淋巴癌中的一种或几种;优选的所述癌症为具体癌症为结肠癌,所述炎症为结肠炎。
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