CN114380813B - 一种vista靶向的探针及其制备方法和应用 - Google Patents
一种vista靶向的探针及其制备方法和应用 Download PDFInfo
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- CN114380813B CN114380813B CN202210051416.0A CN202210051416A CN114380813B CN 114380813 B CN114380813 B CN 114380813B CN 202210051416 A CN202210051416 A CN 202210051416A CN 114380813 B CN114380813 B CN 114380813B
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Abstract
一种VISTA靶向的探针及其制备方法和应用，涉及医药化学领域，靶向化合物为VISTA抑制剂分子和核素标记基团以特定的化学形式相连接。本发明还提供基于该靶向化合物的放射性核素标记的诊疗探针，其按湿法或冻干法进行制备。本发明还涉及所述探针在人或动物肿瘤或免疫性疾病中作为诊疗试剂的用途，其具有制备简单、稳定性好、病灶摄取高等优点，适于临床推广。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种靶向V型免疫球蛋白结构域的T细胞活化抑制因子(VISTA)的化合物及其核素标记的疾病诊疗探针。
背景技术
免疫学的发展为肿瘤等重大疾病的治疗带来了革命性的变化，已经成为继手术、放疗、化疗、靶向治疗后癌症的另一有效治疗手段。以PD-1/PD-L1免疫抑制通路阻断及CAR-T细胞疗法为代表的免疫治疗策略为肿瘤病人带来了福音。但受限于免疫微环境的异质性，其治疗效果还无法最大化。V型免疫球蛋白结构域的T细胞活化抑制因子(VISTA,V-DomainImmunoglobulin-Containing Suppressor of T Cell Activation)是一个十分引人注目的靶点。VISTA也称PD-1H(Programmed Death-1homolog，即PD-1同源物)，属于免疫球蛋白家族，胞外结构域和PD-L1同源，是一种表达在造血系大多数细胞亚群上的免疫调节受体，常被认为是多种癌症预后不良的指标。VISTA是负调节T细胞反应的一种新型免疫调节分子。VISTA的广泛表达意味着在调节免疫系统反应和区分免疫调节受体的前景方面具有重要的稳态作用，相比其他免疫检查点拥有更高的非冗余活性，是一个非常具有前景的肿瘤免疫治疗靶点，其在调节T细胞活性和肿瘤免疫方面的作用越来越受到重视。除了肿瘤微环境的特性外，VISTA靶向治疗的一个富有希望的方面是VISTA的抑制活性与PD-1/PD-L1通路无关。近些年，免疫检查点，例如PD-1或者CTLA4在控制T细胞的耐受性中起到重要作用。然而，他们往往在T细胞被激活以后才开始表达。关于免疫检查点在维持初始T细胞的静默性和耐受性的作用中的机制是并不明确的。VISTA，作为一种新型的免疫检查点，在初始T细胞中即开始持续表达。因此，敲除VISTA基因会大大上调T细胞介导的抗肿瘤免疫力，同理，阻断VISTA和PD-1/PD-L1能够增强肿瘤免疫功能。
此外，除癌症之外，VISTA也可扮演自身免疫疾病中免疫反应的重要靶标，靶点的特殊之处在于可以同时以阻断型抗体治疗癌症，又可以以激动剂抗体治疗自身免疫病。未来在通过阻断VISTA治疗癌症时，了解哪些自身免疫疾病高表达VISTA，可能有助于预测可能的器官特异性免疫相关不良事件。此外，对VISTA配体或受体的越来越清晰的认识将有利于后续的药物研发。VISTA所扮演的重要角色虽然已引起强烈关注，但大多数相关研究仍是建立在病理组织样本的基础上，在活体层面缺乏可视化的评估手段及特异性探针，这也大大阻碍了该靶点的研究进展。此外，令人生畏的免疫生物学复杂性与向患者尽快提供最有效的免疫疗法的需求相矛盾。随着个体化治疗及精准免疫研究的不断深入，开发针对免疫关键靶点VISTA的新型放射性诊疗探针意义重大。相对于体外诊断，在体影像学诊断由于其非侵入性、高敏感性、低毒性以及快速的诊断能力，成为诊断研究的重中之重。以Immuno-PET/SPECT为代表的影像学手段为及时、准确地评估疾病发生发展演进过程中微环境的变化、制定更精准的免疫治疗方案提供了一把利器。利用高分辨分子影像技术，结合高灵敏高特异性的分子探针，有望从分子水平反映肿瘤病变情况，具有活检和生物标志物检测所不能企及的优势。特别是近年来，大部分的免疫检查点抑制剂及其对应放射性核素标记探针都是基于单克隆抗体的药物，其较长的血液半衰期成为进一步应用的制约因素。目前，在临床上广泛应用的18F标记氟代脱氧葡萄糖(18F-FDG)-PET成像已成为肿瘤诊断、分期和疗效监测的重要手段。遗憾的是，18F-FDG在正常心脑组织的高摄取、无法区分免疫靶点、易受患者血糖及葡萄糖转运蛋白低表达水平影响等成为该成像技术的明显不足。因此，针对VISTA靶点开发放射性核素新探针显得十分必要。鉴于VISTA靶向药物在多种临床前肿瘤模型中具有显著的治疗作用，通过更为灵活多变的小分子免疫检点抑制剂探针来实现活体层面的VISTA可视化，将解决该靶点研究中存在的缺憾与空白。
发明内容
本发明的目的在于解决现有技术中的上述问题，提供一种VISTA靶向的探针及其制备方法和应用。
为达到上述目的，本发明采用如下技术方案：
一种VISTA靶向的探针基于VISTA化合物，所述VISTA化合物的结构如下式(1)所示：
其中，R1为核素标记基团，核素包括177Lu、90Y、18F、64Cu、68Ga、62Cu、67Cu、64Gd、86Y、89Zr、99mTc、89Sr，153Sm、149Tb、161Tb、186Re、188Re、212Pb、213Bi、223Ra、225Ac、226Th、227Th、123/124/125/131I、211At或111In中的至少一种。
所述核素选自68Ga、99mTc、18F、177Lu、90Y及225Ac中的至少一种。
所述核素通过式(I)化合物中的核素标记基团R1进行螯合。
所述核素标记基团R1通过如下带核素结构引入核素123/124/125/131I或18F，
所述核素标记基团R1选自以下任意一种结构：
本发明中，当式(I)中R1分别采用以下结构时：
所述VISTA化合物分别为DNCA、NNCA、DCA、NCA、HCA，其结构分别如下所示：
本发明所述一种VISTA靶向的探针，其制备方法采用湿法或冻干法进行制备。
所述湿法步骤如下：将式(1)化合物溶于缓冲溶液或去离子水中，然后加入含放射性核素的溶液，室温至100℃反应10～30min，然后用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
所述冻干法步骤如下：将式(1)化合物溶于缓冲溶液或去离子水中，分装于冻干容器中，经冷冻干燥后密封成冻干药盒，可根据需要在冻干药盒加入相关赋形剂、抗氧化剂或酸碱调节剂；在冻干药盒中加入去离子水或缓冲液溶解，再加入含放射性核素的溶液，室温至100℃反应10～30min，用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
本方明VISTA靶向的探针的应用于制备检测或治疗与VISTA相关的疾病或病症的产品中的应用；所述VISTA靶向的探针被制备成注射剂，通过静脉注射给药；所述的病症包括肿瘤或自身免疫疾病；所述肿瘤包括乳腺癌、卵巢癌、肺癌、结直肠癌、前列腺癌、肺癌、纤维肉瘤、骨骼及结缔组织肉瘤、肾细胞癌、胃癌、胰腺癌或皮肤黑色素瘤等；所述自身免疫疾病包括红斑狼疮、类风湿性关节炎、肝炎、自身免疫性脑脊髓炎、硬皮症、银屑病、干燥综合征、结节性多动脉炎、哮喘等；显像诊断方式包括单光子发射计算机断层成像术(SPECT)和正电子发射断层成像术(PET)。所述的治疗可包括核素靶向治疗、免疫治疗或联合治疗。
相对于现有技术，本发明技术方案取得的有益效果是：
本发明提供的探针是精准免疫学的重要补充，填补VISTA核素靶向探针领域的空白，适合用于肿瘤等疾病的免疫微环境生物标志物在体筛查，避免离体标本的分子病理检测，为肿瘤等重大疾病的可视化诊断鉴别、监测治疗及评估预后提供有效新途径。更有助于构建围绕VISTA靶点的“炎-癌转化体系及免疫关系网络”，并以此为基础探索肿瘤及其相关疾病的治疗机制。生物数据表明，本发明中的探针具有靶向性强、靶/非靶比值高等优点，有利于该类探针的商业化应用与临床推广。
附图说明
图1为化合物NNCA的质谱图。
图2为化合物DNCA的质谱图。
图3为化合物HCA的质谱图。
图4为化合物NNCA的HPLC谱图。
图5为化合物DNCA的HPLC谱图。
图6为化合物HCA的HPLC谱图。
图7为配合物68Ga-DNCA的HPLC谱图及其在生理盐水中的稳定结果图。
图8为配合物99mTc-HCA的HPLC谱图及其在生理盐水中的稳定性结果图。
图9为68Ga-DNCA在荷B16黑色素瘤、CT26结肠癌、4T1乳腺癌及PANC02胰腺癌小鼠中0.5h的MicroPET显像图。
具体实施方式
为了使本发明所要解决的技术问题、技术方案及有益效果更加清楚、明白，以下结合附图和实施例，对本发明做进一步详细说明。除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
本发明中FAPI化合物的结构式如下(I)所示：
其中：R1为核素标记基团；核素包括177Lu、90Y、18F、99mTc、64Cu、68Ga、225Ac、89Zr、62Cu、67Cu、64Gd、86Y、89Sr，153Sm、149Tb、161Tb、186Re、188Re、212Pb、213Bi、223Ra、226Th、227Th、123/124/125/ 131I、211At或111In中的至少一种，优选68Ga、99mTc、18F、177Lu、90Y及225Ac中的至少一种。
所述核素通过VISTA靶向化合物结构中的核素标记基团R1进行螯合。
对于金属离子，所述放射性标记探针可以通过含放射性核素的化合物与式(I)化合物按照湿法或冻干法法制备得到。
所述湿法步骤如下：将所述VISTA靶向化合物溶于缓冲溶液或去离子水中，然后加入含放射性核素的溶液，室温至100℃反应10～30min，然后用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
所述冻干法步骤如下：将所述VISTA靶向化合物溶于缓冲溶液或去离子水中，分装于冻干容器中，经冷冻干燥后密封成冻干药盒，可根据需要在冻干药盒加入相关赋形剂、抗氧化剂或酸碱调节剂；在冻干药盒中加入去离子水或缓冲液溶解，再加入含放射性核素的溶液，室温至100℃反应10～30min，用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
具体地，冻干法中分装用容器优选为冻存管或管制抗生素瓶，还可根据药盒冻干粉成型情况选择在药盒中增加赋形剂或抗氧化剂，比如甘露醇、抗坏血酸等，并通过调节VISTA靶向化合物及赋形剂的用量，使药盒成型达到最佳。所述缓冲溶液为稳定反应液pH值的物质，可以为醋酸盐、乳酸盐、酒石酸盐、苹果酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐、碳酸盐和磷酸盐，以及它们的混合物等。
如标记率及放射化学纯度较低，本发明提供一种优选纯化方式为：取一Sep-PakC18分离小柱，先后通过10mL无水乙醇及10mL水进行活化淋洗。加水稀释反应液后经Sep-Pak C18色谱柱分离纯化，以缓冲液或水冲洗色谱柱以除去未反应的放射性离子，以乙醇溶液淋洗得到放射性核素标记的配合物，通过氮吹除去有机溶剂，再经生理盐水或注射用水稀释后无菌过滤，即得到放射化学纯度较高的放射性标记配合物的注射液。
实施例1：
以式(I)结构为基础的前体化合物DNCA或DNCA或HCA或DCA或NCA的合成包括以下步骤：
将p-SCN-Bn-NOTA或p-NCS-Bz-DOTA-GA或HYNIC-NHS或DOTA-NHS或NOTA-NHS和化合物1溶于DMSO或者DMF溶液中，加入适量DIPEA，室温反应4～12h。产品经HPLC分离纯化，收集目标物馏分并冻干，得到对应的化合物NNCA、DNCA、HCA、DCA或NCA。经质谱分析确认目标产物。化合物NNCA、DNCA或HCA的质谱分析图谱及HPLC图谱如图1～6所示。
其余基于(I)结构的VISTA靶向化合物的制备方法均可参考以上合成过程，其区别在于替换相应的核素标记基团，即可得到相应的化合物结构。
本实施例以式(I)结构为基础的前体化合物DNCA或DNCA或HCA或DCA或NCA的合成合成路线如下所示：
实施例2：
68Ga核素标记过程如下：
湿法：将约37～3700MBq 68GaCl3盐酸溶液(淋洗自锗镓发生器)加入到含0.5～2mL实施例2制备的DNCA(20～200μg)的醋酸-醋酸盐溶液的离心管中，置于室温至100℃下反应20分钟后冷却至室温，用生理盐水或注射用水稀释，并经无菌过滤即得标记化合物注射液。
冻干法：将一定量的缓冲液及约37～3700MBq的68GaCl3盐酸溶液(淋洗自锗镓发生器)加入到含DNCA(20～200μg)的冻干药盒中，混匀溶解后置于室温至100℃下反应20min后冷却至室温，用生理盐水或注射用水稀释，并经无菌过滤即得标记化合物注射液。
如放射化学纯度低于95％，则需进行纯化，纯化步骤为：取一Sep-Pak C18分离小柱，先后通过10mL无水乙醇及10mL水进行活化淋洗。用10mL水将标记液稀释后，上样到分离柱上。用水冲洗分离柱除去未反应的68Ga离子，再用乙醇溶液淋洗得到68Ga标记的配合物。通过氮吹除去有机溶剂，经生理盐水稀释后无菌过滤即得标记化合物注射液。
如图7所示，对所标记化合物68Ga-DNCA取样进行HPLC分析鉴定，其放射化学纯度大于95％。
实施例3：
99mTc核素标记：采用SnCl2作为还原剂，N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠盐(TPPTS)作为协同配体进行99mTc的标记。
湿法：将新鲜配制的SnCl2溶液(SnCl2的盐酸溶液)20μL加入到含有20～200μg HCA化合物、1～50mg Tricine及1～10mg TPPTS的溶液中，随后立即加入37～7400MBq新鲜淋洗的Na99mTcO4洗脱液(淋洗自钼锝发生器)，混匀后压盖密封，室温至100℃下反应30分钟后冷却至室温，用生理盐水或注射用水稀释，并经无菌过滤即得标记化合物注射液。
冻干法：将约37～3700MBq新鲜的Na99mTcO4洗脱液(淋洗自钼锝发生器)加入到含有20-200μg HCA化合物，1～50mg Tricine及1～10mg TPPTS的冻干药盒中(含甘露醇及抗坏血酸)，混匀后压盖密封，室温至100℃下反应30分钟后冷却至室温，用生理盐水或注射用水稀释，并经无菌过滤即得标记化合物注射液。
如放射化学纯度低于95％，则需进行纯化，纯化步骤为：取一Sep-Pak C18分离小柱，先后通过10mL无水乙醇及10mL水进行活化淋洗。用10mL水将标记液稀释后，上样到分离柱上。用水冲洗分离柱除去未反应的99mTcO4 -，再用乙醇溶液淋洗得到99mTc标记的配合物。通过氮吹仪除去有机溶剂，经生理盐水稀释后无菌过滤即得标记化合物99mTc-HCA注射液。
如图8所示，对所标记化合物99mTc-HCA取样进行HPLC分析鉴定，其放射化学纯度大于95％。
实施例4：
1.脂水分布系数(log P)测定
将100μL稀释后的99mTc-HCA或68Ga-DACA加入到含有2.9mL PBS和3mL正辛醇混合液的离心管中，涡旋震荡3min之后，6000rpm离心5min，从水相及正辛醇相中各取100μL液体并通过γ-counter放射性计数。实验重复三次取平均值。log P的计算公式为：
P＝I有机相/I水相
其中I有机相代表有机相中测定的放射性计数、I水相代表水相中测定的放射性计数。通过计算，最终测定各放射性标记的靶向探针的脂水分布系数。所测标记化合物99mTc-HCA及68Ga-DACA的logP值分别为-2.76及-2.63，均呈现水溶性。
2.体外稳定性测试
将用生理盐水溶解的标记化合物68Ga-DNCA或99mTc-HCA在室温下放置不同时间，取样用HPLC进行分析。在所测试时间点，探针依旧保持放射化学纯>95％，表明其在指定溶液中性质稳定，不易分解。68Ga-DNCA及99mTc-HCA生理盐水的稳定性HPLC鉴定结果如图7及图8所示，表明其在该体系中保持较高的稳定性(>95％)。
实施例5：
肿瘤模型鼠MicroPET显像
按实施例2制备好放射化学纯度大于95％的68Ga-DNCA标记配合物溶液，取0.2mL(约11MBq)通过荷B16黑色素瘤、CT26结肠癌、4T1乳腺癌及PANC02胰腺癌小鼠尾静脉进行注射，于注射后30分钟时间点进行MicroPET成像。由图9所示，箭头所指区域为肿瘤位置处，本发明68Ga标记探针68Ga-DNCA在小鼠肿瘤中有明显富集及滞留，在肌肉、肝脏、血池等正常组织器官中清除较快，靶与非靶比值高。膀胱位置有较高的放射性信号，这意味着探针体内代谢经尿液排出体外。
本发明提供的探针是精准免疫学的重要补充，填补VISTA核素靶向探针领域的空白，适合用于肿瘤等疾病的免疫微环境生物标志物在体筛查，避免离体标本的分子病理检测，为肿瘤等重大疾病的可视化诊断鉴别、监测治疗及评估预后提供有效新途径。更有助于构建围绕VISTA靶点的“炎-癌转化体系及免疫关系网络”，并以此为基础探索肿瘤及其相关疾病的治疗机制。生物数据表明，本发明中的探针具有靶向性强、靶/非靶比值高等优点，有利于该类探针的商业化应用与临床推广。
Claims (7)
1.一种VISTA靶向的探针，其特征在于：该探针基于VISTA化合物，所述VISTA化合物的结构如下式(1)所示：
其中，R1为核素标记基团，选自以下任意一种结构：
核素选自177Lu、90Y、64Cu、68Ga、89Zr、99mTc、188Re、213Bi、223Ra、225Ac、211At或111In中的至少一种。
2.如权利要求1所述的一种VISTA靶向的探针，其特征在于：所述核素选自68Ga、99mTc、177Lu、90Y及225Ac中的至少一种。
3.如权利要求1所述的一种VISTA靶向的探针，其特征在于：所述核素通过式(I)化合物中的核素标记基团R1进行螯合。
4.权利要求1～3任一项所述的一种VISTA靶向的探针的制备方法，其特征在于：采用湿法或冻干法进行制备。
5.如权利要求4所述的制备方法，其特征在于所述湿法步骤如下：将式(1)化合物溶于缓冲溶液或去离子水中，然后加入含放射性核素的溶液，室温至100℃反应10～30min，然后用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
6.如权利要求4所述的制备方法，其特征在于所述冻干法步骤如下：将式(1)化合物溶于缓冲溶液或去离子水中，分装于冻干容器中，经冷冻干燥后密封成冻干药盒，根据需要在冻干药盒加入相关赋形剂、抗氧化剂或酸碱调节剂，所述相关赋形剂采用甘露醇，所述抗氧化剂采用抗坏血酸，所述酸碱调节剂采用醋酸盐、乳酸盐、酒石酸盐、苹果酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐、碳酸盐和磷酸盐中的至少一种；在冻干药盒中加入去离子水或缓冲液溶解，再加入含放射性核素的溶液，室温至100℃反应10～30min，用生理盐水或注射用水稀释，进无菌滤膜过滤即生成放射性核素标记的配合物注射液。
7.权利要求1～3任一项所述的VISTA靶向的探针或者权利要求4～6任一项制备方法所制备的VISTA靶向的探针的应用，其特征在于：应用于制备检测与VISTA相关的疾病或病症的产品中的应用；所述VISTA靶向的探针被制备成注射剂，通过静脉注射给药；所述的病症包括肿瘤或自身免疫疾病；所述肿瘤包括乳腺癌、卵巢癌、肺癌、结直肠癌、前列腺癌、纤维肉瘤、骨骼及结缔组织肉瘤、肾细胞癌、胃癌、胰腺癌或皮肤黑色素瘤；所述自身免疫疾病包括红斑狼疮、类风湿性关节炎、肝炎、自身免疫性脑脊髓炎、硬皮症、银屑病、干燥综合征、结节性多动脉炎、哮喘。
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