CN113861190A - 一种靶向p2x7受体的pet显像剂及其制备方法、组合物及用途 - Google Patents
一种靶向p2x7受体的pet显像剂及其制备方法、组合物及用途 Download PDFInfo
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Abstract
本发明涉及一种放射性诊断药物，并公开了一种靶向P2X7受体的PET显像剂及其制备方法；本发明还公开了含有上述PET显像剂的组合物及用途。本发明的PET显像剂为新型F‑18标记的靶向P2X7受体的PET显像剂，可应用于可应用于监测动脉粥样硬化斑块中炎症进展及外周炎症和肺部肿瘤的鉴别，合成简单、易于临床转化和推广应用。
Description
技术领域
本发明涉及放射性诊断药物领域，特别是涉及一种18F标记的P2X7受体显像剂及其制备方法、组合物及用途。
背景技术
P2X受体是三磷酸腺苷(ATP)门控的离子通道，在哺乳动物中已克隆出7种亚型(P2X1～7)。其中P2X7受体因在多个系统炎症性疾病的病理过程中产生重要作用，近年来备受关注。P2X7受体在体内广泛分布，主要在巨噬细胞和小胶质细胞的细胞膜上高表达，其病理生理作用受ATP的调控，参与巨噬细胞或小胶质细胞的极化过程，主要发挥促进炎症反应和细胞毒性的作用。P2X7受体独特的生理功能，使其成为AD、PD、癫痫、肿瘤等疾病的治疗靶点。因此，有学者提出P2X7可作为小胶质细胞激活和炎症显像的潜在靶点。
目前已有部分P2X7受体拮抗剂用于针对P2X7受体PET显像，但这些显像剂基本上是由11C标记，11C较短的半衰期限制了药物在体内的分布，且其较高的正电子射线能量使得C-11PET图像质量不如F-18药物的图像。18F具有足够长的半衰期，显像图像好，便于临床生产和运输。因此，18F标记的化合物比11C标记的化合物具有更广泛的临床应用和接受度。18F-乙基或18F-苯基取代反应是常规将18F连接在有机分子化合物的方法。目前报道的18F标记的P2X7分子探针例如18F-IUR-1601和18F-EFB均是使用上述常规的18F标记方法。但是，这两种常规方法通常需要经过多步放射化学合成反应才能得到目标产物。此外，由18F-乙基取代反应得到的产物在碱性或高温条件下可能不稳定。因此，复杂的合成路线和较差的分子稳定性限制了两个显像剂的应用。
发明内容
本发明的目的在于针对现有技术的不足，提供一种利用F-18来标记能与P2X7受体特异性结合的分子，根据P2X7受体在炎症和肿瘤中表达量的不同，利用PET/CT来无创地辨别炎症和肿瘤及监测动脉粥样硬化斑块中炎症进展情况。
本发明为实现上述目的采用的技术方案是：一种靶向P2X7受体的PET显像剂，具有如式(I)所示结构：
本发明还提供了如上所述的靶向P2X7受体的PET显像剂的前体，具有如式(II)所示结构：
本发明还提供了所述的靶向P2X7受体的PET显像剂的制备方法，
式II化合物与吡啶、三氟甲磺酸铜混合，与18F反应，经柱分离得到式I化合物。
进一步地，所述式II化合物与吡啶、三氟甲磺酸铜混合的步骤具体为将吡啶加入溶于二甲基乙酰胺的三氟甲磺酸铜中得到混合液，将混合液与溶于二甲基乙酰胺的式II化合物混合。
进一步地，反应温度为150℃，反应时间为10min。
本发明还提供了如上所述的靶向P2X7受体的PET显像剂的前体的制备方法，
式III化合物在四(三苯基膦)钯存在下与六甲基二锡反应制得式II化合物。
进一步地，具体为向含有式III化合物的1,4-二氧六环溶液中加入含有四(三苯基膦)钯的1,4-二氧六环溶液，搅拌后在氮气条件下加入溶于1,4-二氧六环的六甲基二锡溶液，加热并搅拌后过滤浓缩。
本发明还提供了一种组合物，其包含如上所述的式I化合物作为活性成分。
本发明还提供了如上所述的靶向P2X7受体的PET显像剂用于鉴别外周炎症和肿瘤的用途。
本发明还提供了如上所述的靶向P2X7受体的PET显像剂用于监测动脉粥样硬化斑块中炎症进展的用途
本发明的优点和效果：
1)和18F标记的脂肪族氟化物相比，18F标记的芳基氟化物相当稳定，本实验通过一步取代反应将目标分子的三甲基锡基团取代，把18F连接在目标分子上，标记方法简便，合成化合物稳定；
2)通过改造前体，利用铜盐催化的芳基锡化物的氟化反应得到18F-FTTM，该制备方法简便，合成化合物稳定，放化学产率和比活度较前增高；
3)本发明F-18标记的P2X7受体拮抗剂的放射性标记物，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，可作为检测体内P2X7受体的放射性显像剂。
附图说明
图1为18F-FTTM药代动力学曲线；
图2为18F-FTTM细胞结合饱和曲线；
图3为18F-FTTM在动脉粥样斑块模型鼠和外周炎症模型鼠的显像结果。
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。
本发明实施例中使用的反应物和催化剂均为化学纯，可直接使用或根据需要经过简单纯化；有机溶剂等均为分析纯，直接使用。
试剂均购自中国医药(集团)上海化学试剂公司。
主要检测仪器：
核磁共振仪型号：(Bruker 400MHz)；
质谱仪(液质联用(LCMS))，型号：(Shimadzu,LCMS-2020)。
实施例1
前体pre-FTTM的合成：
在氮气下，向含有800.0mg化合物6的13mL 1,4-二氧六环溶液中添加溶于6mL二氧六环的Pd(PPh3)4溶液，25℃下搅拌5分钟，然后在氮气下，向6mL 1,4-二氧六环中加入1.87g六甲基二锡，与前述混合物混合加热至100℃并搅拌3小时。经LC-MS检测后，通过过滤浓缩，得到粗产物。通过制备型HPLC(柱：Xtimate C18 150×40mm×10μm；流动相：[水(10mMNH4HCO3)-ACN]；B％：35％-65％，10min)纯化粗产物。
前体pre-FTTM的氢谱数据如下：δ8.90-8.85(m,2H),7.46-7.39(m,3H),7.28-7.23(m,1H),5.15-5.08(m,1H),4.62-4.52(m,1H),4.22-4.11(m,1H),3.61-3.60(m,1H),3.59-3.25(m,2H)。
实施例2
化合物18F-FTTM的合成：
将吡啶(1M，0.1mL)加入溶于无水二甲基乙酰胺(DMA)的三氟甲磺酸铜(Cu(OTf)2,0.2M，67μL)中，将其混合液与溶于DMA的pre-FTTM(1.5-3mg)混合后添加到含有干燥的18F的反应瓶中进行反应(反应条件为150℃，加热10分钟)。反应结束后，待反应液冷却后，加入1mL水淬灭反应，通过C-18和Al2O3 Sep-Pak柱分离后经制备Radio-HPLC(乙腈/水＝4.0/6.0，含0.1％三氟乙酸)得到18F-FTTM。所得反应产物用LC-MS进行化学表征检测，用分析型Radio-HPLC测得放射性产物的放射化学纯度大于99％、比活度为269-320MBq/nmol，计算放射化学产率为5％-10％(衰变校正)。
实施例3
18F-FTTM的体外稳定性实验：
以实施例2所得的18F-FTTM约10μCi分别置于100μL 0.9％生理盐水及0.1％BSA中，充分混匀后37℃下存放。分别在1、2、4和6小时取样，在分析型HPLC上检验其纯度变化。结果见表1。
表1化合物18F-FTTM在生理盐水和FBS中的HPLC检测结果
结果表明，化合物18F-FTTM非常稳定，在6h内未见明显分解。
实施例4
18F-FTTM的药代动力学实验；
以实施例2所得的18F-FTTM约200μCi经尾静脉注射进10只8周雄性裸鼠体内，分别于注射后1、3、5、10、20、30、45、60、90和120min时断尾，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。结果如图1所示。
实施例5
18F-FTTM与P2X7受体结合试验：
将实施例2所得的18F-FTTM(37kBq/0.5ml每孔)加入24孔板中的RAW264.7巨噬细胞(每孔约1～5×106个)中，将浓度范围在5-200nM的18F-FTTM按浓度梯度加入含与上述含有巨噬细胞的24孔板中，孵育2h后分别收集上清液和细胞悬液进行γ计数器计数，以加入100μM的FTTM冷化合物组为非特异性结合，得到结合饱和曲线。结果如图2所示。通过曲线可知，18F-FTTM与表达P2X7受体的RAW264.7巨噬细胞有较好的亲和力。
实施例6
18F-FTTM的生物分布实验：
以实施例2所得的18F-FTTM约100μCi经尾静脉注射进8周龄雄性裸鼠20只，麻醉状态下，采取摘取眼球取血方式，分别在15、30、60和90min时各处死5只裸鼠，收集感兴趣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18F-FTTM的相对吸收值。结果见表2。
表2化合物18F-FTTM的生物分布检测结果
实施例7
18F-FTTM的活体显像试验：
以实施例2所得的18F-FTTM约100μCi/只通过3组高脂喂养20周的APOE-/-动脉粥样硬化斑块模型鼠、右后肢肌肉注射松节油外周炎症模型鼠和右前肢皮下荷瘤模型鼠，在持续麻醉状态下进行PET/CT显像。结果如图3所示，研究发现在PET/CT图像中，显像剂18F-FTTM可浓集于炎症模型鼠右后肢的炎症肌肉组织中，而椭圆框内所示的肿瘤组织未见明显显像剂摄取，动脉粥样硬化斑块模型鼠主动脉可见点状18F-FTTM显像剂摄取。
上述实验表明，本发明合成的化合物18F-FTTM稳定性强，能够特异性地结合P2X7受体，并且结合稳定性较强，可作为检测体内P2X7受体的放射性显像剂用于PET/CT无创地辨别炎症和肿瘤，识别动脉粥样硬化斑块，为F-18标记的靶向P2X7受体PET显像剂的科学研究和临床应用奠定基础。
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)
1.一种靶向P2X7受体的PET显像剂，其特征在于，具有如式(I)所示结构：
2.如权利要求1所述的靶向P2X7受体的PET显像剂的前体，其特征在于，具有如式(II)所示结构：
3.一种如权利要求1所述的靶向P2X7受体的PET显像剂的制备方法，其特征在于，
式II化合物与吡啶、三氟甲磺酸铜混合，与18F反应，经柱分离得到式I化合物。
4.如权利要求3所述的PET显像剂的制备方法，其特征在于，所述式II化合物与吡啶、三氟甲磺酸铜混合的步骤具体为将吡啶加入溶于二甲基乙酰胺的三氟甲磺酸铜中得到混合液，将混合液与溶于二甲基乙酰胺的式II化合物混合。
5.如权利要求3所述的PET显像剂的制备方法，其特征在于，反应温度为150℃，反应时间为10min。
6.一种如权利要求1所述的靶向P2X7受体的PET显像剂的前体的制备方法，其特征在于，
式III化合物在四(三苯基膦)钯存在下与六甲基二锡反应制得式II化合物。
7.如权利要求6所述的前体的制备方法，其特征在于，具体为向含有式III化合物的1,4-二氧六环溶液中加入含有四(三苯基膦)钯的1,4-二氧六环溶液，搅拌后在氮气条件下加入溶于1,4-二氧六环的六甲基二锡溶液，加热并搅拌后过滤浓缩。
8.一种组合物，其包含如权利要求1中所述的式I化合物作为活性成分。
9.如权利要求1所述的靶向P2X7受体的PET显像剂用于鉴别肺部炎症和肿瘤的用途。
10.如权利要求1所述的靶向P2X7受体的PET显像剂用于监测动脉粥样硬化斑块中炎症进展的用途。
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