CN110770212B - 用于前列腺癌诊断的18f标记的化合物及其用途 - Google Patents
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- CN110770212B CN110770212B CN201880041217.3A CN201880041217A CN110770212B CN 110770212 B CN110770212 B CN 110770212B CN 201880041217 A CN201880041217 A CN 201880041217A CN 110770212 B CN110770212 B CN 110770212B
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Abstract
本发明涉及一种18F标记的化合物及其用途。所述化合物选择性地结合前列腺特异性膜抗原(PSMA),且在用于正电子放射断层造影术(PET)中时使得可在短时间内获取清晰的前列腺癌图像。
Description
发明领域
本发明涉及一种用于前列腺癌诊断的18F标记的化合物及其用途。
背景技术
前列腺癌是美国男性癌症致死的主要病因,在韩国位列第五且在世界范围内位列第二。前列腺癌通常在50岁以上男性中出现,但患者数量随年龄而快速增加。它通常发展缓慢,但当其发展至恶性转移时,则极难治愈。转移通常自前列腺癌周围的淋巴结、骨盆、脊椎和膀胱开始,并逐渐扩散至全身。
目前主要使用前列腺特异性抗原检测(PSA检测(PSA test))和直肠指检进行前列腺癌诊断,并且也使用经直肠超声检查、CT、MRI和WBBS(全身骨扫描(Whole body bonescan))成像。也进行活组织检查来进行前列腺癌诊断。然而,在大多数情形下,诊断准确率低且对疾病的早期诊断较为困难。另外,难以确定转移且难以与诸如前列腺增生和前列腺炎等良性疾病相区别。
正电子放射断层造影术(Positron Emission Tomography,PET)是一种使用靶向疾病特异性代谢或蛋白的分子探针(Molecular probes)的人类成像方法。这种方法通过使用半衰期短的放射性同位素观察疾病早期阶段的生物化学变化而在早期诊断、治疗评估和确认转移/复发方面具有优势。
[18F]FDG是一种用于癌症诊断的代表性PET放射性药物,因为它可观察癌细胞增强的葡萄糖代谢。在下文的专利参考文献1中公开了此类技术的一种实例。然而,在前列腺癌的情形下,[18F]FDG的摄取量并不高,使其难以用于前列腺癌诊断。另外,诸如[18F]氟胆碱(fluorocholine)、[11C]乙酸盐(acetate)和[18F]FACBC等化合物已应用于前列腺癌诊断。然而,在使用它们时,诊断准确率并不高,且难以观察到转移的小尺寸前列腺癌。
前列腺特异性膜抗原(Prostate-Specific Membrance Antigen,PSMA)是一种在前列腺癌中特异性过度表达的蛋白质,而且已知谷氨酸-尿素-赖氨酸(glutamic acid-Urea-lysine,GUL)的尿素基二肽化合物极具选择性地与其结合。已研发出若干种以GUL基放射性同位素标记的化合物作为前列腺癌特异性的诊断药物。
其中,18F-DCFPyL是一种18F同位素标记的GUL化合物,且被评估为用于前列腺癌诊断的最佳PET示踪剂之一。所述18F-DCFPyL与先前研发的化合物(18F-DCFBzL)相比具有相对低的亲脂特性,因此使其在活体内具有低的非特异性结合特性,且经过肾快速去除。
最近进一步研发出一种称为18F-YC88的化合物。它是一种与18F-DCFPyL化合物相比具有较低亲脂特性的化合物,通过进一步减少非特异性结合来表征并且被快速去除。然而,此化合物的问题在于与PSMA蛋白的结合力相比于18F-DCFPyL减少约10倍,且前列腺癌信号随时间流逝而大幅减小。
【现有技术参考文献】
韩国专利公布No.10-2016-0085769、韩国专利公布No.10-2011-0038725
发明内容
本发明的目标在于提供一种能够准确诊断前列腺癌的18F标记的化合物及其用途。
本发明的目标不局限于上述目标。本发明的目标将由以下描述更显而易见,且将通过权利要求书中描述的方式及其组合来实现。
根据本发明的一种实施方案的化合物由下式1来表示。
在式1中,Y为C1-C5亚烷基;和Z为-CH2-(CH2-O-CH2)n-CH2-,其中n为0至5的整数;R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基;且F可为18F或19F。
Y为C1-C2亚烷基,且F可为18F。
根据本发明的另一种实施方案的化合物由下式11来表示。
在式11中,Y为C1-C5亚烷基;且R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基。
Y可为C1-C2亚烷基。
根据本发明的另一种实施方案的一种用于治疗或诊断前列腺癌的药物组合物包含式1的化合物或其药学上可接受的盐。
根据本发明的另一种实施方案的一种用于对前列腺癌进行影像诊断的放射性药物包含式1的化合物或其药学上可接受的盐。
影像诊断可包括正电子放射断层造影术(PET)。
有益效果
根据本发明的一种实施方案,18F所结合的式1化合物具有高亲水性、良好的活体内药代动力学特性和低的非特异性结合,以便在短时间内可获得清晰的正电子放射断层造影术(PET)图像。
附图说明
图1A和1B是说明根据化合物[18F]1-6的制备步骤的放射性TLC结果的示意图。
图2是说明根据化合物[18F]1-6的制备步骤的HPLC分离结果的示意图。
图3是说明前列腺癌小鼠的MicroPET/CT结果的示意图。
图4A至4C是说明肌肉、肝和脾的摄入比与肿瘤相比的图表。
图5A和5B是说明器官生物分布随时间变化的图表。
具体实施方式
通过结合附图的以下优选实施例,易于理解本发明的以上目标、其它目标、特征和优势。然而,本发明不限于本文所述的实施例,并且可通过其它形式具体化。相反,提供本文中所引入的实施例以便可完整且全面地实施本发明,并将本发明的精神全部传达给本领域技术人员。
下文详细描述由本发明的式1所表示的一种化合物。
本发明包括一种由下式1表示的化合物。
在式1中,
Y为C1-C5亚烷基;
Z为-CH2-(CH2-O-CH2)n-CH2-,其中n为0至5的整数;
R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基;且
F可为18F或19F。
更具体来说,Y为C1-C2亚烷基;
Z为-CH2-(CH2-O-CH2)n-CH2-,其中n为0至5的整数;
R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基;且
F可为18F。
本发明的式1的配位体可另外通过亲脂键与PSMA蛋白结合,因为亲脂键在结构上可与芳香族芳基结合。另外,18F所结合的侧链中的三唑基可增加化合物的极性以减小活体内非特异性结合。
本发明的此类经氟18标记的化合物可同时具有良好的与PSMA蛋白质结合的能力以及良好的药代动力学特性。
本发明提供一种用于治疗或诊断前列腺癌的药物组合物,其包含式1的化合物或其药学上可接受的盐作为活性成分。
本发明还提供一种诊断性放射性药物在需要对前列腺癌进行治疗性监控或影像诊断的受试者中的用途。用于影像诊断的此类放射性药物可包括式1的化合物或其药学上可接受的盐作为活性成分。本文中,影像诊断可包括磁共振成像(MRI)或正电子放射断层造影术(PET),且优选地可使用正电子放射断层造影术(PET)来进行。
在上述化合物中,放射性配位体被摄入表达PSMA的前列腺癌组织中且可在其它器官中去除,以便可在短时间内清晰地获得PET图像。
下文详细描述一种由本发明的式11表示的化合物。
本发明包括一种由下式11表示的化合物。
在式11中,
Y为C1-C5亚烷基;且
R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基。
更具体来说,Y为C1-C2亚烷基;且
R为氢或具有取代基的C1-C2烷基,其中所述取代基为含有一个或多个选自O、S和N元素的C6-C12芳基或C4-C10杂芳基。
实施例1.制备N-丙胺基(propazyl)胺衍生物
下文反应式1中展示本发明的一种示意性反应过程。
实施例1-1.制备化合物3(步骤1)
将4-氨基吡啶(2,9.0g,96mmol)溶解于二氯甲烷(400mL)中,在0℃下向其中添加(Boc)2O(25.0g,110mmol)。向其中缓慢添加三乙胺(20.0mL,140mmol),紧接着在室温下搅拌2小时。向其中添加水且使用二氯甲烷将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(7%甲醇/二氯甲烷)纯化。因此,获得白色固体状的化合物3(18.0g,97%)。
1H NMR(400MHz,CDCl3)δ1.53(s,9H),7.29(brs,1H),7.34(dd,J=4.8,1.6Hz,2H),8.44(dd,J=4.8,1.6Hz,2H);
13C NMR(100MHz,CDCl3)δ28.2,81.6,112.3,145.8,150.4,152.0;MS(ESI)m/z 193[M-H]-
实施例1-2.制备化合物4(步骤2)
将上文步骤1中合成的化合物3(18.0g,93mmol)溶解于二甲基甲酰胺(DMF,400mL)中,在0℃下向其中添加氢化钠(7.4g,900mmol)。向其中缓慢添加溴丙胺(Propazylbromide),紧接着在室温下搅拌2小时。在0℃下向其中添加甲醇(50ml),紧接着搅拌30分钟。向其中添加水且使用乙酸乙酯将有机化合物萃取三次。将收集的有机溶剂用氯化铵水溶液洗涤三次、经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(5%甲醇/二氯甲烷)纯化。因此,获得浅黄色固体状的化合物4(13.4g,62%)。
1H NMR(400MHz,CDCl3)δ1.53(s,9H),2.31(t,J=2.6Hz,1H),4.43(d,J=2.4Hz,2H),7.38(d,J=5.2Hz,2H),8.54(m,2H);
13C NMR(100MHz,CDCl3)δ28.1,38.5,72.4,79.1,82.7,118.0,149.2,150.2,152.6;MS(ESI)m/z 233[M+H]+
实施例1-3.制备化合物5(步骤3)
将含有4N HCl的二恶烷(75mL)添加至上文步骤2中合成的化合物4(13.0g,56mmol)中,紧接着在室温下搅拌6小时。向其中添加2N氢氧化钠水溶液(500ml)且使用二氯甲烷将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(60%乙酸乙酯/二氯甲烷,NH硅胶)纯化。因此,获得浅黄色固体状的化合物5(6.8g,92%)。
1H NMR(400MHz,CDCl3)δ2.27(t,J=2.6Hz,1H),3.97(dd,J=6.0,2.4Hz,2H),4.66(brs,1H),6.53(dd,J=4.8,1.6Hz,2H),8.26(dd,J=4.4,1.6Hz,2H);
13C NMR(100MHz,CDCl3)δ32.4,72.0,79.4,108.1,150.1,152.3;MS(ESI)m/z 133[M+H]+
实施例2.制备化合物8(N-丙胺基,N-(吡啶-4-基甲基)胺)
将4-吡啶甲醛(7,0.5mL,4.7mmol)溶解于二氯甲烷(10mL)中,向其中添加丙胺基胺(0.31mL,5.6mmol)。向其中缓慢添加三乙酰氧基硼氢化钠(1.5g,7.05mmol),紧接着在室温下搅拌2小时。向其中添加水且使用二氯甲烷将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(2%甲醇/二氯甲烷)纯化。因此,获得亮红色液体状的化合物8(315mg,46%)。
1H NMR(400MHz,CDCl3)δ2.28(t,J=2.4Hz,1H),3.45(d,J=2.4Hz,2H),3.93(s,2H),4.24(brs,1H),7.32(dd,J=5.2,0.8Hz,2H),8.57(dd,J=5.2,0.8Hz,2H);
13C NMR(100MHz,CDCl3)δ37.4,50.8,72.1,81.3,123.3,148.8,149.4;MS(ESI)m/z147[M+H]+
下文反应式2中展示本发明的一种示意性反应过程。
实施例3.制备N-丙胺基胺-尿素-GUL化合物
下文反应式3中展示本发明的一种示意性反应过程。
实施例3-1.制备化合物10-1
将三光气(107mg,0.36mmol)溶解于乙腈(5.0mL)中,在0℃下向其中缓慢添加溶解于乙腈(10mL)中的谷氨酸-尿素-赖氨酸(9,500mg,1.03mmol)。向其中添加三乙胺(0.50mL,3.61mmol),紧接着搅拌30分钟。在0℃下向其中添加丙胺基胺(0.072mL,1.13mmol)。15分钟后,将混合物在室温下搅拌1小时,且然后在减压下浓缩。向其中添加水且使用乙酸乙酯将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(2%甲醇/二氯甲烷)纯化。因此,获得白色固体状的化合物10-1(492mg,84%)。
1H NMR(400MHz,CDCl3)δ1.25-1.30(m,2H),1.44(s,18H),1.48(s,9H),1.51-1.60(m,3H),1.67-1.76(m,1H),1.80-1.90(m,1H),2.05-2.13(m,1H),2.18(t,J=2.6Hz,1H),2.29-2.40(m,2H),3.06-3.12(m,1H),3.30-3.36(m,1H),3.95-4.06(m,2H),4.08-4.14(m,1H),4.36(sext,J=4.4Hz,1H),5.64(d,J=7.6Hz,1H),5.69(t,J=5.2Hz,1H),5.89(t,J=5.4Hz,1H),6.11(d,J=8.4Hz,1H);
13C NMR(100MHz,CDCl3)δ23.4,27.7,27.8,27.9,28.0,29.6,29.7,31.7,32.1,39.4,53.3,54.2,70.5,80.7,81.4,81.5,83.1,158.0,158.2,172.0,172.3,174.6;MS(ESI)m/z 569[M+H]+
实施例3-2.制备化合物10-2
通过如实施例3-1中所述的相同方式获得浅黄色固体状的化合物10-2(270mg,66%),不同之处在于使用溶解于乙腈(3.0mL)中的三光气(64mg,0.211mmol)、溶解于乙腈(6mL)中的谷氨酸-尿素-赖氨酸(9,300mg,0.62mmol)、三乙胺(0.302mL,2.17mmol)和在实施例2中合成的化合物8(100mg,0.68mmol)。
1H NMR(400MHz,CDCl3)δ1.22-1.30(m,2H),1.43(s,9H),1.45(s,18H),1.48-1.54(m,2H),1.59-1.64(m,1H),1.71-1.77(m,1H),1.79-1.88(m,2H),2.03-2.09(m,1H),2.27-2.32(m,1H),2.35(t,J=2.2Hz,1H),3.24(sept,J=6.2Hz,2H),4.07(t,J=2.4Hz,2H),4.27-4.35(m,2H),4.60(dd,J=20.4,17.2Hz,2H),4.92(s,1H),5.24(d,J=7.6Hz,1H),5.44(d,J=8.0Hz,1H),7.24(d,J=5.2Hz,2H),8.60(d,J=4.8Hz,2H);
13C NMR(100MHz,CDCl3)δ22.3,27.9,28.0,28.1,28.4,29.4,31.6,32.4,36.8,40.7,49.6,53.0,53.3,73.4,78.8,80.5,81.7,82.0,122.3,147.0,150.2,157.0,157.7,172.3,172.4,172.5;MS(ESI)m/z 660[M+H]+
实施例3-3.制备化合物10-3
将实施例1-3中合成的化合物5(200mg,1.51mmol)溶解于乙腈(5.0mL)中,在0℃下向其中缓慢添加溶解于乙腈(5.0mL)中的4-硝基氯甲酸苯酯(305mg,1.51mmol)。向其中添加三乙胺(0.50mL,3.61mmol),紧接着搅拌30分钟。在0℃下向其中缓慢添加溶解于乙腈(10mL)中的谷氨酸-尿素-赖氨酸(9,886mg,1.82mmol),且然后再向其中添加二异丙胺(0.324mL,1.82mmol)。15分钟后,将混合物在100℃下搅拌12小时。将混合物冷却至室温后,向其中添加水且使用乙酸乙酯将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(5%甲醇/二氯甲烷)纯化。因此,获得无色液体状的化合物10-3(836mg,86%)。
1H NM(400MHz,CDCl3)δ1.27-1.37(m,2H),1.43(s,9H),1.45(s,18H),1.50-1.55(m,2H),1.59-1.65(m,1H),1.72-1.88(m,2H),2.01-2.10(m,1H),2.27-2.34(m,1H),2.35(t,J=2.4Hz,1H),2.16(q,J=6.7Hz,2H),4.25-4.34(m,2H),4.50(ddd,J=25.2,18.0,2.4Hz,2H),5.21(t,J=5.8Hz,1H),5.48(s,1H),5.50(s,1H),7.32(dd,J=4.8,1.6Hz,2H),8.59(d,J=6.4Hz,2H);
13C NMR(100MHz,CDCl3)δ22.4,27.9,28.0,28.1,28.3,29.4,31.6,32.4,38.2,40.7,52.9,53.3,72.9,79.3,80.5,81.6,82.0,119.5,149.6,151.2,155.3,157.1,172.3,172.4,172.5;MS(ESI)m/z 646[M+H]+
下文反应式4中展示本发明的一种示意性反应过程。
实施例4.化合物10的去保护基
下文反应式5中展示本发明的一种示意性反应过程。
实施例4-1.制备化合物11-1
将在实施例3-1中合成的化合物10-1(450mg,0.79mmol)溶解于60%三氟乙酸/二氯甲烷(2mL)中,紧接着在室温下搅拌4小时。将反应物在减压下浓缩并通过高效液相色谱法(HPLC)纯化。因此,获得白色固体状的化合物11-1(280mg,88%)。
1H NMR(400MHz,DMSO-d6)δ1.24-1.29(m,2H),1.32-1.39(m,2H),1.46-1.55(m,1H),1.60-1.67(m,1H),1.68-1.77(m,1H),1.84-1.92(m,1H),2.24(td,J=7.8,2.6Hz,2H),2.96(q,J=6.4Hz,2H),3.01(t,J=2.6Hz,1H),3.77(dd,J=5.6,2.4,2H),4.05(sext,J=7.6Hz,2H),5.98(t,J=5.6Hz,1H),6.13(t,J=5.6,1H),6.31(d,J=8.4Hz,2H),12.43(brs,3H);
13C NMR(100MHz,D2O)δ21.4,25.6,27.8,28.5,29.3,29.9,38.7,52.0,52.6,70.5,80.4,118.2,158.3,159.2,175.6,176.4;MS(ESI)m/z 399[M-H]-
实施例4-2.制备化合物11-2
将实施例3-2中合成的化合物10-2(460mg,0.70mmol)溶解于60%三氟乙酸/二氯甲烷(2mL)中,紧接着在室温下搅拌4小时。将反应物在减压下浓缩并通过高效液相色谱法(HPLC)纯化。因此,获得白色固体状的化合物11-2(289mg,84%)。
1H NMR(400MHz,D2O)δ1.10-1.18(m,2H),1.29-1.36(m,2H),1.44-1.52(m,1H),1.56-1.63(m,1H),1.71-1.80(m,1H),1.91-1.99(m,1H),2.28(t,J=7.4Hz,2H),2.56(t,J=2.4Hz,1H),3.03(td,J=6.6,2.0Hz,2H),3.89(dd,J=8.6,5.0Hz,1H),3.98(dd,J=8.6,5.0Hz,1H),4.06(d,J=2.4Hz,2H),4.72(s,2H),7.78(d,J=5.6Hz,2H),8.55(d,J=4.8Hz,2H);
13C NMR(100MHz,D2O)δ22.3,27.3,28.7,30.6,31.3,37.7,40.2,50.9,53.9,54.3,74.0,78.6,124.8,140.9,158.7,158.8,159.2,160.3,178.0,178.6;MS(ESI)m/z 492[M+H]+
实施例4-3.制备化合物11-3
将实施例3-3中合成的化合物10-3(650mg,1.01mmol)溶解于中60%三氟乙酸/二氯甲烷(3mL),紧接着在室温下搅拌4小时。将反应物在减压下浓缩并通过高效液相色谱法(HPLC)纯化。因此,获得白色固体状的化合物11-3(390mg,81%)。
1H NMR(400MHz,D2O)δ1.21-1.26(m,2H),1.38-1.43(m,2H),1.46-1.53(m,1H),1.58-1.67(m,1H),1.69-1.74(m,1H),1.84-1.93(m,1H),2.22(t,J=7.6Hz,2H),2.61(t,J=0.8Hz,1H),3.12(t,J=6.6Hz,2H),3.92(q,J=6.5Hz,2H),4.45(s,2H),7.44(d,J=6.4Hz,2H),8.27(d,J=4.0Hz,2H);
13C NMR(100MHz,D2O)δ22.4,27.1,27.7,30.5,31.2,37.9,40.6,53.6,54.1,74.8,76.5,114.5,140.7,156.1,156.2,159.0,177.7,177.9,178.4;MS(ESI)m/z 478[M+H]+
实施例5.通过点击化学制备氟-三唑-尿素-GUL化合物
下文反应式6中展示本发明的一种示意性反应过程。
实施例5-1.制备化合物1-1
将2-氟乙基甲苯磺酸酯(FCH2CH2OTs,82mg,0.38mmol)溶解于二甲基甲酰胺(0.2mL)中,向其中添加叠氮化钠(73mg,1.13mmol),紧接着在60℃下搅拌12小时来合成氟乙基叠氮化物(12-1)。将反应溶液过滤并用乙醇(0.3mL)洗涤。向滤液中添加溶解实施例4-1中合成的化合物11-1(30mg,0.075mmol)的水溶液(0.5mL)。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.046mL,0.023mmol)和抗坏血酸钠水溶液(0.5M,0.076mL,0.038mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-1(7mg,19%)。
1H NMR(400MHz,D2O)δ1.17-1.28(m,2H),1.30-1.37(m,2H),1.50-1.59(m,1H),1.64-1.72(m,1H),1.77-1.87(m,1H),1.98-2.05(m,1H),2.36(t,J=7.4Hz,2H),2.96(t,J=6.4Hz,2H),4.03(dd,J=8.4,4.8Hz,1H),4.11(dd,J=8.8,5.6Hz,1H),4.24(s,2H),4.56-4.57(m,1H),4.65-4.68(m,2H),4.75(t,J=4.6Hz,1H),7.79(s,1H);
13C NMR(100MHz,D2O)δ22.0,26.1,28.5,29.9,30.4,34.9,39.4,50.7(d,J=19Hz),52.5,53.1,81.9(d,J=168Hz),124.0,146.2,159.5,160.2,176.2,177.1,177.2;MS(ESI)m/z 488[M-H]-
实施例5-2.制备化合物1-2
将2-氟乙基甲苯磺酸酯(FCH2CH2OTs,89mg,0.41mmol)溶解于二甲基甲酰胺(0.2mL)中,向其中添加叠氮化钠(79mg,1.22mmol),紧接着在60℃下搅拌12小时来合成氟乙基叠氮化物(12-1)。将反应溶液过滤并用乙醇(0.3mL)洗涤。向滤液中添加溶解实施例4-2中合成的化合物11-2(40mg,0.081mmol)的水溶液(0.5mL)。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.049mL,0.024mmol)和抗坏血酸钠水溶液(0.5M,0.081mL,0.041mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-2(33mg,70%)。
1H NMR(400MHz,D2O)δ1.21-1.34(m,2H),1.41-1.50(m,2H),1.59-1.68(m,1H),1.71-1.80(m,1H),1.86-1.96(m,1H),2.08-2.16(m,1H),2.45(t,J=7.2Hz,2H),3.16(t,J=6.6Hz,2H),4.09(dd,J=8.4,5.2Hz,1H),4.21(dd,J=8.8,5.6Hz,1H),4.63-4.70(m,6H),4.84(s,2H),7.72(d,J=6.0Hz,2H),7.93(s,1H),8.60(dd,J=6.8,1.2Hz,2H);
13C NMR(100MHz,D2O)δ22.1,26.0,28.5,29.9,30.4,40.0,42.6,50.5,50.6(d,J=19Hz),81.9(d,J=168Hz),124.6,124.7,140.6,143.5,159.0,159.2,160.6,176.1,177.0,177.1;MS(ESI)m/z 581[M+H]+
实施例5-3.制备化合物1-3
将2-氟乙基甲苯磺酸酯(FCH2CH2OTs,91mg,0.42mmol)溶解于DMF(0.2mL)中,向其中添加NaN(82mg,1.26mmol),紧接着在60℃下搅拌12小时来合成氟乙基叠氮化物(12-1)。将反应溶液过滤并用乙醇(0.3mL)洗涤。向滤液中添加溶解实施例4-3中合成的化合物11-3(40mg,0.084mmol)的水溶液(0.5mL)。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.050mL,0.025mmol)和抗坏血酸钠水溶液(0.5M,0.084mL,0.042mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-3(27mg,57%)。
1H NMR(400MHz,D2O)δ1.15-1.24(m,2H),1.36-1.43(m,2H),1.49-1.58(m,1H),1.63-1.72(m,1H),1.75-1.84(m,1H),1.96-2.05(m,1H),2.34(t,J=7.4Hz,2H),3.15(t,J=6.6Hz,2H),4.01(dd,J=8.8,5.2Hz,1H),4.10(dd,J=9.0,5.0Hz,1H),4.55-4.61(m,3H),4.73(t,J=4.4Hz,1H),5.05(s,2H),7.47(d,J=7.6Hz,2H),7.92(s,1H),8.27(d,J=7.6Hz,2H);
13C NMR(100MHz,D2O)δ22.2,26.1,27.5,29.9,30.4,40.4,43.2,50.7(d,J=19Hz),52.4,53.0,81.9(d,J=168Hz),114.4,124.7,140.7,142.3,156.4,156.8,159.2,176.1,176.9,177.1;MS(ESI)m/z 567[M+H]+
实施例5-4.制备化合物1-4
将通过将在实施例4-1中合成的化合物11-1(40mg,0.10mmol)溶解在水(0.5mL)中制备的溶液添加至溶解1-叠氮基-2-(2-氟乙氧基)乙烷(12-2,16mg,0.12mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.060mL,0.030mmol)和抗坏血酸钠水溶液(0.5M,0.100mL,0.050mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-4(20mg,38%)。
1H NMR(400MHz,D2O)δ1.14-1.22(m,2H),1.24-1.32(m,2H),1.45-1.54(m,1H),1.59-1.66(m,1H),1.72-1.82(m,1H),1.93-2.02(m,1H),2.31(t,J=7.2Hz,2H),2.91(t,J=6.8Hz,2H),3.51(td,J=4.0,0.8Hz,1H),3.58(td,J=4.0,0.8Hz,1H),3.81(t,J=4.8Hz,2H),3.98(dd,J=8.8,4.8Hz,1H),4.06(dd,J=9.2,5.2Hz,1H),4.20(s,2H),4.28(td,J=4.0,0.8Hz,1H),4.39(td,J=4.0,0.8Hz,1H),4.45(t,J=4.68Hz,2H),7.78(s,1H);
13C NMR(100MHz,D2O)δ22.0,26.0,28.4,29.9,30.4,34.7,39.4,50.3,52.4,53.0,68.6,69.7(d,J=18Hz),83.1(d,J=162Hz),124.3,145.8,159.2,160.1,176.1,177.0,177.1;MS(ESI)m/z 534[M+H]+
实施例5-5.制备化合物1-5
将通过将实施例4-2中合成的化合物11-2(40mg,0.081mmol)溶解在水(0.5mL)中制备的溶液添加至溶解有1-叠氮基-2-(2-氟乙氧基)乙烷(12-2,13mg,0.097mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.049mL,0.024mmol)和抗坏血酸钠水溶液(0.5M,0.081mL,0.041mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-5(37mg,72%)。
1H NMR(400MHz,D2O)δ1.16-1.23(m,2H),1.33-1.40(m,2H),1.52-1.60(m,1H),1.63-1.70(m,1H),1.81-1.88(m,1H),2.00-2.07(m,1H),2.38(t,J=7.4Hz,2H),3.07(t,J=6.8Hz,2H),3.57(t,J=4.0Hz,1H),3.65(t,J=4.0Hz,1H),3.83(t,J=5.0Hz,2H),4.02(dd,J=8.4,5.2Hz,1H),4.14(dd,J=9.0,5.0Hz,1H),4.34(t,J=4.0Hz,1H),4.45-4.49(m,3H),4.59(s,2H),4.75(s,2H),7.69(d,J=6.8Hz,2H),7.86(s,1H),8.55(d,J=6.8Hz,2H);
13C NMR(100MHz,D2O)δ22.2,26.2,28.6,29.9,30.5,40.1,42.7,49.9,50.6,52.5,53.2,68.7,69.7(d,J=19Hz),83.2(d,J=163Hz),124.7,124.9,140.7,143.5,159.1,159.2,160.7,176.1,177.0,177.1;MS(ESI)m/z 625[M+H]+
实施例5-6.制备化合物1-6
将通过将实施例4-3中合成的化合物11-3(40mg,0.084mmol)溶解在水(0.5mL)中制备的溶液添加至溶解有1-叠氮基-2-(2-氟乙氧基)乙烷(12-2,13mg,0.10mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.050mL,0.025mmol)和抗坏血酸钠水溶液(0.5M,0.084mL,0.042mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-6(38mg,75%)。
1H NMR(400MHz,D2O)δ1.20-1.28(m,2H),1.40-1.47(m,2H),1.54-1.62(m,1H),1.66-1.74(m,1H),1.77-1.86(m,1H),1.98-2.08(m,1H),2.36(t,J=7.4Hz,2H),3.17(t,J=6.8Hz,2H),3.52(t,J=3.8Hz,1H),3.60(t,J=4.0Hz,1H),3.83(t,J=5.0Hz,2H),4.05(dd,J=8.8,4.8Hz,1H),4.12(dd,J=9.2,5.2Hz,1H),4.28(t,J=4.0Hz,1H),4.40(t,J=3.8Hz,1H),4.48(t,J=5.0Hz,2H),5.06(s,2H),7.48(d,J=7.6Hz,2H),7.90(s,1H),8.28(d,J=7.6Hz,2H);
13C NMR(100MHz,D2O)δ22.3,26.2,27.6,29.9,30.5,40.5,43.3,50.0,52.5,53.1,68.7,69.7(d,J=19Hz),83.1(d,J=163Hz),114.4,124.7,140.7,142.1,156.4,156.8,159.2,176.1,176.9,177.1;MS(ESI)m/z 611[M+H]+
实施例5-7.制备化合物1-7
将通过将实施例4-1中合成的化合物11-1(40mg,0.10mmol)溶解在水(0.5mL)中制备的溶液添加至溶解有1-叠氮基-2-(2-(2-氟乙氧基)乙氧基)乙烷(12-3,21mg,0.12mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.060mL,0.030mmol)和抗坏血酸钠水溶液(0.5M,0.100mL,0.050mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-3(50mg,77%)。
1H NMR(400MHz,D2O)δ1.16-1.26(m,2H),1.28-1.36(m,2H),1.49-1.58(m,1H),1.63-1.71(m,1H),1.76-1.85(m,1H),1.97-2.06(m,1H),2.35(t,J=7.4Hz,2H),2.94(t,J=6.4Hz,2H),3.49-3.50(m,5H),3.57(td,J=4.0,1.2Hz,1H),3.81(t,J=4.8Hz,2H),4.02(dd,J=8.8,4.8Hz,1H),4.10(dd,J=9.0,5.4Hz,1H),4.24(s,2H),4.34(td,J=4.4,1.2Hz,1H),4.45-4.49(m,3H),7.84(s,1H);
13C NMR(100MHz,D2O)δ22.0,26.1,28.4,29.9,30.4,34.6,39.4,50.5,52.4,53.0,68.4,69.3,69.4,69.7(d,J=19Hz),83.1(d,J=163Hz),124.5,145.5,159.2,160.1,176.2,177.0,177.1;MS(ESI)m/z 578[M+H]+
实施例5-8.制备化合物1-8
将通过将实施例4-2中合成的化合物11-2(40mg,0.081mmol)溶解在水(0.5mL)中制备的溶液添加至溶解有1-叠氮基-2-(2-(2-氟乙氧基)乙氧基)乙烷(12-3,17mg,0.097mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.049mL,0.024mmol)和抗坏血酸钠水溶液(0.5M,0.081mL,0.041mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-8(47mg,87%)。
1H NMR(400MHz,D2O)δ1.13-1.25(m,2H),1.36(quint,J=7.0Hz,2H),1.50-1.60(m,1H),1.63-1.72(m,1H),1.79-1.88(m,1H),2.00-2.09(m,1H),2.38(t,J=7.2Hz,2H),3.07(t,J=6.8Hz,2H),3.52(s,4H),3.54(t,J=4.0Hz,1H),3.62(t,J=4.0Hz,1H),3.80(t,J=5.2Hz,2H),4.02(dd,J=8.6,5.4Hz,1H),4.14(dd,J=9.0,5.0Hz,1H),4.38(t,J=4.0Hz,1H),4.46-4.51(m,3H),4.58(s,2H),4.75(s,2H),7.70(d,J=6.4Hz,2H),7.88(s,1H),8.55(d,J=6.8Hz,2H);
13C NMR(100MHz,D2O)δ22.2,26.2,28.6,30.0,30.5,40.1,42.7,50.0,50.6,52.5,53.2,68.6,69.4,69.5,69.7(d,J=19Hz),83.3(d,J=162Hz),124.7,124.9,140.8,143.5,159.1,159.2,160.7,176.1,177.0,177.1;MS(ESI)m/z 669[M+H]+
实施例5-9.制备化合物1-9
将通过将实施例4-3中合成的化合物11-3(40mg,0.084mmol)溶解在水(0.5mL)中制备的溶液添加至溶解有1-叠氮基-2-(2-(2-氟乙氧基)乙氧基)乙烷(12-3,18mg,0.10mmol)的乙醇(0.5mL)中。向其中逐步添加CuSO4·5H2O水溶液(0.5M,0.050mL,0.025mmol)和抗坏血酸钠水溶液(0.5M,0.084mL,0.042mmol),紧接着在室温下搅拌1小时。将反应混合物过滤并用水洗涤。然后通过HPLC分离滤液。因此,获得白色固体状的化合物1-9(30mg,55%)。
1H NMR(400MHz,D2O)δ1.15-1.22(m,2H),1.35-1.40(m,2H),1.47-1.56(m,1H),1.61-1.68(m,1H),1.72-1.81(m,1H),1.93-2.03(m,1H),2.31(t,J=7.2Hz,2H),3.12(t,J=6.6Hz,2H),3.43(s,4H),3.46(t,J=4.0Hz,1H),3.54(t,J=4.0Hz,1H),3.75(t,J=4.8Hz,2H),3.99(dd,J=8.8,5.2Hz,1H),4.07(dd,J=9.2,5.2Hz,1H),4.30(t,J=4.0Hz,1H),4.41-4.44(m,3H),5.00(s,2H),7.43(d,J=7.6Hz,2H),7.87(s,1H),8.24(d,J=7.2Hz,2H);
13C NMR(100MHz,D2O)δ22.2,26.1,27.5,29.9,30.4,40.4,43.2,50.0,52.4,53.0,68.6,69.3,69.4,69.7(d,J=18Hz),83.1(d,J=162Hz),114.3,124.6,140.6,142.0,156.3,156.8,159.2,176.1,176.9,177.1;MS(ESI)m/z 655[M+H]+
实施例6.合成125I-MIP1095化合物
下文反应式7中展示本发明的一种示意性反应过程。
实施例6-1.制备化合物13(步骤1)
将三光气(21mg,0.071mmol)溶解于二氯甲烷(5mL)中,在0℃下向其中缓慢添加溶解于二氯甲烷(5mL)中的4-碘苯胺(45mg,0.205mmol)。向其中添加三乙胺(0.57mL,0.410mmol),紧接着搅拌30分钟。在0℃下向其中缓慢添加溶解于二氯甲烷(10mL)中的谷氨酸-尿素-赖氨酸(9,100mg,0.205mmol)。还向其中添加三乙胺(0.57mL,0.410mmol)。15分钟后,将混合物在室温下搅拌5小时。将混合物在减压下浓缩并通过柱色谱法(2%甲醇/二氯甲烷)纯化。因此,获得白色液体状的化合物13(66mg,44%)。
1H NMR(400MHz,CDCl3)δ1.20-1.27(m,2H),1.37(s,9H),1.40(s,9H),1.44(s,9H),1.47-1.57(m,2H),1.71-1.81(m,2H),1.83-1.91(m,1H),2.03-2.11(m,1H),2.37(sext,J=8.2Hz,2H),3.01-3.07(m,1H),3.51-3.56(m,1H),3.97-4.01(m,1H),4.26-4.32(m,1H),5.75(d,J=7.2Hz,1H),6.31(q,J=3.4Hz,1H),6.40(d,J=8.0Hz,1H),7.27(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),7.90(s,1H);
13C NMR(100MHz,CDCl3)δ24.5,27.1,27.8,27.9,28.0,29.6,31.7,32.0,39.1,53.8,54.9,81.0,81.8,83.6,83.7,120.2,137.5,140.2,155.6,158.5,171.8,172.0,175.3;MS(ESI)m/z 733[M+H]+
实施例6-2.制备化合物14(步骤2)
将上文步骤1中合成的化合物13(50mg,0.068mmol)溶解于1,4-二恶烷(1.0mL)中,向其中逐步添加六甲基二锡(0.043mL,0.206mmol)和双(三苯基膦)二氯化钯(II)(4.8mg,0.005mmol),紧接着在110℃下搅拌1.5小时。将混合物冷却至室温后,向其中添加氟化钾水溶液(50mL)且使用乙酸乙酯将有机化合物萃取三次。将收集的有机溶剂经无水硫酸钠干燥、在减压下浓缩并通过柱色谱法(三乙胺:乙酸乙酯:正己烷,1:40:59)纯化。因此,获得白色固体状的化合物14(28mg,53%)。
1H NMR(400MHz,CDCl3)δ0.25(s,9H),1.22-1.29(m,2H),1.38(s,9H),1.41(s,9H),1.43(s,9H),1.48-1.59(m,2H),1.72-1.78(m,1H),1.81-1.91(m,1H),2.05-2.13(m,2H),2.34-2.43(m,2H),3.04-3.09(m,1H),3.51-3.55(m,1H),4.04(pent,J=4.9Hz,1H),4.33(sext,J=4.5Hz,1H),5.73(d,J=6.8Hz 1H),6.23(br s,1H),6.32(d,J=8.4Hz,1H),7.35(d,J=8.0Hz,2H),7.43(d,J=8.4Hz,2H),7.73(s,1H);
13C NMR(100MHz,CDCl3)δ-9.5,24.2,27.4,27.8,27.9,28.0,29.7,31.8,32.1,39.1,53.7,54.7,80.9,81.7,83.5,118.4,133.6,136.2,140.4,155.9,158.3,171.9,172.2,175.1;MS(ESI)m/z 771[M+2H]+
实施例7.制备18F标记的化合物([18F]1)
下文反应式8中展示本发明的一种示意性反应过程。
实施例7-1.制备[18F]1-1化合物
将蒸馏水(3mL)倾倒至(HCO3)上,使其穿过[18F]氟化物水溶液(508mCi),且然后向其中倾倒乙醇(1mL)。将Krytofix222-甲烷磺酸钾(10mg)溶解于乙醇(1mL)中,使Chromafix经其穿过,并通过在100℃下向溶液中吹入氮气去除溶剂。将2-叠氮基4-甲苯磺酸乙酯15-1(1.2mg)溶解于叔丁醇(500μL)中,将其放置在含有[18F]氟化物的反应容器中,紧接着在100℃下反应10分钟(制备[18F]12-1)。将反应混合物冷却至室温。然后,将150μL(137mCi)的反应混合物放置在另一个反应容器中,向其中依次添加乙醇(150μL)、其中溶解有化合物11-1(1mg)的水溶液(100μL)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-1(55.3mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),70分钟;流速,4mL/min.;UV,230mm;滞留时间,15-20分钟。
实施例7-2.制备[18F]1-2化合物
将150μL(122mCi)的其中溶解有实施例7-1中制备的[18F]12-1的叔丁醇放置在另一反应容器中,向其中依次添加乙醇(150μL)、其中溶解有化合物11-2(1.5mg)的水溶液(100μL)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-2(39mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA)50分钟;流速,4mL/min.;UV,230mm;滞留时间,17-20分钟。
实施例7-3.制备[18F]1-3化合物
将200μL(120mCi)的其中溶解有实施例7-1制备的[18F]12-1的叔丁醇放置在另一反应容器中,向其中依次添加乙醇(150μL)、其中溶解有化合物11-3(1.5mg)的水溶液(100μL)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-3(19.9mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),90分钟;流速,4mL/min.;UV,230mm;滞留时间,14-16分钟。
实施例7-4.制备[18F]1-4化合物
将蒸馏水(3mL)倾倒至(HCO3)上,使其穿过[18F]氟化物水溶液(493mCi),且然后向其中倾倒乙醇(1mL)。将Krytofix222-甲烷磺酸钾(10mg)溶解于乙醇(1mL)中,使Chromafix经其穿过,并通过在100℃下向溶液中吹入氮气去除溶剂。将2-(2-叠氮基乙氧基)甲烷磺酸乙酯15-2(2.2mg)溶解于叔丁醇(500μL)中,将其放置在含有[18F]氟化物的反应容器中,紧接着在100℃下反应10分钟(制备[18F]12-2)。将反应混合物冷却至室温。然后,将150μL(81.3mCi)的反应混合物放置在另一个反应容器中,向其中依次添加乙醇(150μL)、其中溶解有化合物11-1(2mg)的水溶液(100μL)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-4(16.8mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),70分钟;流速,4mL/min.;UV,254mm;滞留时间,26-29分钟。
实施例7-5.制备[18F]1-5化合物
将150μL(88.4mCi)的其中溶解有实施例7-4中制备的[18F]12-2的叔丁醇放置在另一反应容器中,向其中依次添加溶解于蒸馏水(100μL)中的化合物11-2(1.5mg)、0.5MCuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-5(26.5mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),50分钟;流速,4mL/min.;UV,254mm;滞留时间,29分钟。
实施例7-6.制备[18F]1-6化合物
将100μL(88.0mCi)的其中溶解有实施例7-4中制备的[18F]12-2的叔丁醇放置在另一反应容器中,向其中依次添加溶解于蒸馏水(100μL)中的化合物11-3(2mg)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-6(16.1mCi)。
图1A、1B和2是说明根据化合物[18F]1-6的制备步骤的放射性TLC和HPLC分离结果的图表。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),50分钟;流速,4mL/min.;UV,254mm;滞留时间,27分钟。
实施例7-7.制备[18F]1-7化合物
将蒸馏水(3mL)倾倒至(HCO3 -)上,使其穿过[18F]氟化物水溶液(574mCi),且然后向其中倾倒乙醇(1mL)。将Krytofix222-甲烷磺酸钾(10mg)溶解于乙醇(1mL)中,使Chromafix经其穿过,并通过在100℃下向溶液中吹入氮气去除溶剂。将2-(2-(2-叠氮基乙氧基)乙氧基)甲烷磺酸乙酯15-3(2.7mg)溶解于叔丁醇(500μL)中,将其放置在含有[18F]氟化物的反应容器中,紧接着在100℃下反应10分钟(制备[18F]12-3)。f反应完成后,通过在100℃下向溶液中轻轻吹入氮气去除溶剂,且然后将反应混合物溶解于乙醇(300μL)中。将100μL(87mCi)的其中溶解有[18F]12-3的乙醇溶液放置在另一反应容器中,向其中依次添加其中溶解有化合物11-1(2mg)的蒸馏水(100μL)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-7(31.2mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),50分钟;流速,4mL/min.;UV,254mm;滞留时间,29分钟。
实施例7-8.制备[18F]1-8化合物
将100μL(87mCi)的其中溶解有实施例7-7制备的[18F]12-3的乙醇溶液(100μL)放置在另一反应容器中,向其中依次添加溶解于蒸馏水(100μL)中的化合物11-2(1.5mg)、0.5M CuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-8(26.5mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),50分钟;流速,4mL/min.;UV,254mm;滞留时间,27分钟。
实施例7-9.制备[18F]1-9化合物
将100μL(89mCi)的其中溶解有实施例7-7制备的[18F]12-3的乙醇溶液(100μL)放置在另一反应容器中,向其中依次添加溶解于蒸馏水(100μL)中的化合物11-3(2mg)、0.5MCuSO4(5μL)和0.5M抗坏血酸钠(10μL),紧接着在室温下反应10分钟。向反应混合物中添加蒸馏水(2mL),将其过滤并通过HPLC进行分离。因此,获得化合物[18F]1-9(18.9mCi)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,5-30%乙腈/水(0.1%TFA),50分钟;流速,4mL/min.;UV,254mm;滞留时间,27.5分钟。
比较实施例1.制备[125I]15([125I]MIP-1095)化合物
将实施例6-2中合成的化合物14(0.1mg)溶解于乙醇(250μL)中,将其添加至碘化钠[125I]水溶液(4.6mCi,50μL)中,紧接着进行搅拌。向其中添加1N HCl水溶液(100μL)和3%H2O2,紧接着在室温下搅拌10分钟。向反应混合物中添加0.1M硫代硫酸钠水溶液(200μL)和蒸馏水(18mL),使其穿过C-18Sep-Pak,紧接着向其中倒入蒸馏水(20mL)。将乙腈(2.0mL)倒入C-18Sep-Pak中,且然后通过向溶液中吹入氮气去除乙腈。向其中添加二氯甲烷(0.2mL)和三氟乙酸(0.8mL),紧接着在室温下搅拌20分钟。通过向溶液中吹入氮气去除反应溶剂。向反应混合物中添加蒸馏水(2mL),将其通过HPLC进行分离。因此,获得化合物[125I]15(1.1mCi,24%)。
HPLC条件:塔,XTerra MS C18(250mm x 10mm);流动相,30%乙腈/水(0.1%TFA);流速,5mL/min;UV,254mm;滞留时间,10.4分钟。
下文反应式9中展示本发明的一种示意性反应过程。
参考实施例1.材料准备
本文中使用的人类前列腺癌细胞系(22RV1)购自美国模式培养物保藏所(American Type Culture Collection,ATCC)。PC3 PIP(PSMA+)和PC3 flu(PSMA-)人类前列腺癌细胞系由Dr.Martin G.Pomper(Johns Hopkins Medical School,Baltimore,MD)提供。将人类前列腺癌细胞系维持在补充有10%胎牛血清(FBS)和1%抗生素/抗真菌剂的RPMI1640培养基中。在PC3 PIP(PSMA+)和PC3 flu(PSMA-)细胞系的培养物中,另外添加浓度为2μg/mL的嘌呤霉素。
使用6周大的雄性裸小鼠(Narabio,Seoul,Korea)作为试验动物。
实验实施例1.测量结合能力
为证明本发明实施例7中获得的18F标记的化合物和比较实施例1中获得的[125I]15与前列腺癌细胞系的结合能力,进行以下实验。
使用补充有1%BSA(牛血清白蛋白)的RPMI1640作为缓冲溶液。
将[125I]15(0.1nM)添加至含有22RV1细胞(5X104)的容器中,以9种浓度(1.00Ⅹ10-4至1.00Ⅹ10-12M)向其中负载[18F]1-1至[18F]1-9化合物,紧接着在37℃下搅拌2小时。搅拌完成后,用2mL的PBS溶液将容器洗涤三次,且然后使用γ射线计数器(2480WIZARD2 GammaCounter PerkinElmer Co.,MA)和GraphPad Prism(GraphPad Software,Inc.,CA)测量剩余的放射性和50%抑制浓度(非线性回归方法)。
表1是展示测量结果的表格。
因此,如表1中所示,吡啶直接与尿素官能团结合的[18F]1-6(实施例7-6)的IC50值最佳(5.08),无吡啶的[18F]1-3(实施例7-3)的IC50值差70倍以上,且结合甲基吡啶的[18F]1-9(实施例7-9)的IC50值差40倍以上。因此证明[18F]1-6(实施例7-6)的吡啶与PSMA蛋白质形成高亲脂键。
将实施例7-4至实施例7-6进行比较。因此证明三唑基与18F同位素之间的距离越长,IC50值越佳。
因此,发现具有直接与尿素结合的吡啶且在18F同位素与三唑基之间具有三乙二醇基的[18F]1-6(实施例7-6)与PSMA蛋白质结合最强烈。
[18F]DCFPyL(比较实施例1)的IC50值为30.71。因此,证明本发明的[18F]1-6(实施例7-6)具有高出约6倍的结合能力。
【表1】
化合物 | IC<sub>50</sub>(平均值±SD,nM) |
比较实施例1 | 30.71±10.18 |
实施例7-1 | 635.13±262.66 |
实施例7-2 | 65.34±39.08 |
实施例7-3 | 391.00±227.94 |
实施例7-4 | 56.99±33.02 |
实施例7-5 | 11.80 |
实施例7-6 | 5.08±2.57 |
实施例7-7 | 64.62±38.44 |
实施例7-8 | 284.10±115.70 |
实施例7-9 | 235.63±190.70 |
实验实施例2.测量细胞内化
为证明本发明实施例7中获得的18F标记的化合物和比较实施例1中获得的[125I]15对于前列腺癌细胞系的细胞内化特征,进行以下实验。
将3.7MBq(100μCi)的实施例7-3、实施例7-6和比较实施例1添加至PC-3PIP(1X106/1mL)中,在30、60和120分钟后将其各自以2mL的PBS溶液洗涤两次。然后,通过使用Mem-PER Plus膜蛋白提取试剂盒和NE-PER细胞核和细胞质提取试剂盒(ThermoFisherScientific)分离膜蛋白与细胞质蛋白。通过获得细胞质蛋白中相对于总放射性的放射性比率来证明内化率。
表2展示细胞内化率。
因此,如表2中所示,证明三种化合物在前列腺癌细胞中均充分内化,无任何显著差异,且内化几乎在前30分钟内即完成,随时间流逝无任何改变。
【表2】
实验实施例3.测量经前列腺癌细胞系移植的小鼠体内的MicroPET/CT
为证明本发明实施例7中获得的18F标记的化合物和比较实施例1中获得的[125I]15对前列腺特异性细胞膜抗体的结合特性,进行以下实验。
通过向裸小鼠后腿右侧皮下注射PSMA+PC-3PIP细胞(人类前列腺癌细胞系)且向裸小鼠后腿左侧皮下注射PSMA-PC-3flu细胞作为对照来制备肿瘤模型。另外,向实施例7-3和实施例7-6各自静脉内注射5.5至7.4MBq(200μL),且使用小动物纳米扫描PET/CT(Mediso,Budapest,Hungary)持续60分钟来获得PET/CT图像。使用InterViewTM FUSION软件(Mediso)对PET/CT图像结果进行定量分析。使用比较实施例1作为对照化合物。
图3是说明前列腺癌小鼠的MicroPET/CT结果的示意图。图4A至4C是说明肌肉、肝和脾的摄入比与肿瘤相比的图表。
如图3中所示,证明实施例7-3、实施例7-6和比较实施例1通过肾和膀胱快速排泄,而且它们选择性地结合PSMA+PC-3PIP肿瘤。如图4A至4C中所示,证明实施例7-3与实施例7-6和比较实施例1相比展示相对更高的肿瘤/肌肉摄入比(肿瘤肌肉比)和肿瘤/肝脏摄入比(肿瘤肝脏比)。
实验实施例4.前列腺癌模型小鼠的生物分布试验
为证明本发明实施例7中获得的18F标记的化合物和比较实施例1中获得的[125I]15在前列腺癌模型小鼠中的生物分布,进行以下实验。
通过向裸小鼠(6周大,20-25g)后腿右侧皮下注射PSMA+PC-3PIP细胞(人类前列腺癌细胞系)且向裸小鼠后腿左侧皮下注射PSMA-PC-3flu细胞作为对照来制备肿瘤模型。合成实施例7-3和实施例7-6的化合物,将其分别以3.7MBq(100μCi)的剂量注射至小鼠的尾静脉中。在30分钟、1小时、2小时和4小时后提取每个器官(血液、肌肉、脂肪、心脏、肝、脾、胃、小肠、肾、骨头和肿瘤)并使用γ射线计数器测量其放射性。
表3和表4展示实施例7-3和实施例7-6的化合物在每个器官中的放射性程度。图5A和5B是说明器官生物分布随时间变化的图表。
因此,如表3和4以及图5A和5B所示,在注射实施例7-3和7-6的化合物30分钟后,肿瘤摄取率(%ID/g)增加至10%以上。另外,证明实施例7-3的化合物与PSMA+肿瘤(PC-3PIP)相比具有更高的PSMA-肿瘤组织(PC-3flu)摄取率且与肿瘤相比具有优越的正常组织摄取率。
【表3】
时间(h) | PIP/flu | PIP与肌肉的比率 | PIP与血液的比率 | PIP与脾的比率 | PIP与肝的比率 |
0.5 | 40.59±9.85 | 47.39±38.05 | 35.64±25.01 | 7.74±6.03 | 17.35±4.34 |
1 | 103.45±9.73 | 86.15±29.07 | 98.69±30.64 | 13.77±5.53 | 15.92±1.95 |
2 | 176.33±65.83 | 334.14±260.49 | 487.24±354.87 | 58.80±53.63 | 18.47±7.63 |
4 | 232.60±71.80 | 533.90±188.93 | 766.82±331.65 | 128.24±95.38 | 20.93±7.40 |
【表4】
时间(h) | PIP/flu | PIP与肌肉的比率 | PIP与血液的比率 | PIP与脾的比率 | PIP与肝的比率 |
0.5 | 16.00±5.68 | 13.00±4.97 | 14.05±3.61 | 7.31±3.34 | 5.64±6.10 |
1 | 23.08±14.91 | 20.11±14.99 | 30.30±17.05 | 12.46±16.18 | 9.93±13.26 |
2 | 33.32±14.64 | 38.11±14.83 | 36.90±9.52 | 25.98±8.66 | 13.71±12.60 |
4 | 35.69±11.64 | 45.39±22.54 | 42.90±18.49 | 32.51±10.12 | 19.77±11.81 |
已根据以上实施方案详细描述本发明。然而,本发明不受以上实施方案限制,且在不偏离本发明精神的情况下可进行各种修改。
Claims (7)
2.根据权利要求1所述的化合物,其中Y为C1-C2亚烷基且F为18F。
4.根据权利要求3所述的化合物,其中Y为C1-C2亚烷基。
5.一种用于治疗或诊断前列腺癌的药物组合物,其包含如权利要求1所述的化合物或其药学上可接受的盐作为活性成分。
6.一种用于对前列腺癌进行影像诊断的放射性药物,其包含如权利要求1所述的化合物或其药学上可接受的盐作为活性成分。
7.根据权利要求6所述的放射性药物,其中所述影像诊断包括磁共振成像或正电子放射断层造影术。
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CA3067696A1 (en) | 2018-12-27 |
AU2018288907B2 (en) | 2020-05-07 |
BR112019027183A2 (pt) | 2020-06-30 |
AU2018288907A1 (en) | 2020-01-23 |
JP2020524175A (ja) | 2020-08-13 |
SG11201911602RA (en) | 2020-01-30 |
EP3643707B1 (en) | 2022-02-23 |
HRP20220557T1 (hr) | 2022-06-10 |
PH12019502665A1 (en) | 2020-10-26 |
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