CN105636924B - 前列腺特异性膜抗原(psma)的标记的抑制剂，它们作为显影剂和用于治疗前列腺癌的药剂的用途 - Google Patents

前列腺特异性膜抗原(psma)的标记的抑制剂，它们作为显影剂和用于治疗前列腺癌的药剂的用途 Download PDF

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CN105636924B
CN105636924B CN201480056250.5A CN201480056250A CN105636924B CN 105636924 B CN105636924 B CN 105636924B CN 201480056250 A CN201480056250 A CN 201480056250A CN 105636924 B CN105636924 B CN 105636924B
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马蒂亚斯·埃德
克劳斯·科普卡
马丁·谢菲尔
乌尔丽克·鲍德-维斯特
乌韦·哈伯科恩
米夏埃尔·艾森胡特
马丁纳·贝内索娃
沃尔特·米尔
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Abstract

本发明总体上涉及放射药剂的领域和它们在核医学中作为示踪物、显影剂和用于治疗各种前列腺癌的疾病状态的用途。因此，本发明涉及由通式(1a)或(1b)表示的化合物。

Description

前列腺特异性膜抗原(PSMA)的标记的抑制剂，它们作为显影 剂和用于治疗前列腺癌的药剂的用途
技术领域
本发明总体上涉及放射性药物领域和它们作为示踪物、显影剂在核医学中的用途以及用于治疗各种前列腺癌的疾病状态。
背景技术
前列腺癌(PCa)是美国和欧洲人口中主要的癌症。在西半球至少1-2百万男性患有前列腺癌，并且据估计，该疾病会侵袭55至85岁之间的六分之一的男性。在美国每年诊断出超过300,000个前列腺癌的新病例。该疾病的死亡率仅次于肺癌。目前的解剖学方法，如计算机断层扫描(CT)、磁共振(MR)成像和超声波占前列腺癌的临床成像的主导地位。估计目前在世界范围内在外科手术、放射、药物疗法和微创治疗上花费了二十亿美元。然而，目前不存在对于复发性、转移性、雄激素非依赖性前列腺癌的有效疗法。
目前临床推行各种实验性的低分子量PCa显影剂，包括放射性标记的胆碱类似物[18F]氟代二羟基睾酮([18F]FDHT)、抗-1-氨基-3-[18F]氟代环丁基-1-羧酸(抗[18F]F-FACBC、[11C]乙酸酯和1-(2-脱氧-2-[18F]氟代-L-阿糖呋喃糖基)-5-甲基尿嘧啶(-[18F]FMAU)(Scher,B.；et al.Eur J Nucl Med Mol Imaging 2007,34,45-53；Rinnab,L；etal.BJU Int 2007,100,786,793；Reske,S.N.；et al.J Nucl Med 2006,47,1249-1254；Zophel,K.；Kotzerke,J.Eur J Nucl Med Mol Imaging 2004,31,756-759；Vees,H.；etal.BJU Int 2007,99,1415-1420；Larson,S.M.；et al.J Nucl Med 2004,45,366-373；Schuster,D.M.；et al.J Nucl Med 2007,48,56-63；Tehrani,O.S.；et al.J Nucl Med2007,48,1436-1441)。每种通过不同的机制运作并具有某些优势，例如[11C]胆碱的低尿排泄，和缺点，如正电子发射放射性核素的短物理半衰期。
众所周知肿瘤可以表达与它们的恶性表型相关的独特蛋白质，或可以以比正常细胞更大的数量过表达正常的组成蛋白。肿瘤细胞表面上的独特蛋白质的表达提供了通过探测该表型标识以及肿瘤的生物化学组合物及活性，诊断和表征疾病的可能性。选择性地结合至特定肿瘤细胞表面蛋白质的放射性分子提供了用于在非侵入条件下成像和治疗肿瘤的有吸引力的途径。有希望的新系列的低分子量显影剂靶标是前列腺特异性膜抗原(PSMA)(Mease R.C.et al.Clin Cancer Res.2008,14,3036-3043；Foss,C.A.；et al.ClinCancer Res 2005,11,4022-4028；Pomper,M.G.；et al.Mol Imaging 2002,1,96-101；Zhou,J.；etr al.Nat Rev Drug Discov 2005,4,1015-1026；WO 2013/022797)。
PSMA是在PCa表面上，特别是在雄激素非依赖性的、晚期的(advanced)和转移性的疾病中具有大量的且受限的表达的，跨膜的，750氨基酸II型糖蛋白(Schulke,N.；etal.Proc Natl Acad Sci U S A2003,100,12590-12595)。后者是重要的，因为几乎所有的PCa会随时间变为雄激素非依赖性的。PSMA拥有用于治疗，即呈现于细胞表面但不脱落到循环系统，并且与酶或信号活性相关的，在疾病的所有阶段大量的且受限(于前列腺)的表达的有希望的靶标的标准(Schulke,N.；et al.Proc.Natl.Acad.Sci.U S A2003,100,12590-12595)。PSMA基因位于染色体11的短臂并起叶酸水解酶和神经肽酶的作用。其具有相当于称作“大脑PSMA”的谷氨酸羧肽酶II(GCPII)的神经肽酶功能，并且通过将N-乙酰基天冬氨酰基谷氨酸酯(NAAG)剪切为N-乙酰基天冬氨酸(NAA)和谷氨酸来调节谷氨酸能传递(glutamatergic transmission)(Nan,F.；et al.J Med Chem 2000,43,772-774)。每个癌细胞存在最多达106个PSMA分子，进一步表明其对于使用基于发射性核素的技术的成像和治疗是理想的靶标(Tasch,J.；et al.Crit Rev Immunol 2001,21,249-261)。
抗-PSMA单克隆抗体(mAb)7E11的放射性免疫结合物，称为扫描，目前用于诊断前列腺癌的转移和复发。然而，该试剂趋向于产生对于解释有挑战性的图像(Lange,P.H.PROSTASCINT scan for staging prostate cancer.Urology 2001,57,402-406；Haseman,M.K.；et al.Cancer Biother Radiopharm 2000,15,131-140；Rosenthal,S.A.；et al.Tech Urol 2001,7,27-37)。已经新近开发出结合至PSMA的胞外域，并且已经放射性标记并在动物中示出聚集在PSMA阳性的前列腺肿瘤模型中的单克隆抗体。然而，使用单克隆抗体的诊断和肿瘤检测已被实体瘤中单克隆抗体的低渗透性限制。
对于成像或治疗目的，用放射性药物选择性靶向癌细胞是挑战性的。已知各种对放射性成像或癌放射疗法有用的放射性核素，包括111In、90Y、68Ga、177Lu、99mTc、123I和131I。近来已经示出，一些含有与放射性核素-配体结合物相连的谷氨酸-脲-谷氨酸(GUG)或谷氨酸-脲-赖氨酸(GUL)识别元素(recognition element)的化合物展现出对PSMA的高亲合性。
需要可以迅速可视化前列腺癌并特异靶向以允许放射线疗法存在的新试剂。
因此，本发明的目标是开发与PSMA相互作用并携带适当的放射性核素的配体，其提供用于检测、治疗和管理前列腺癌的有希望的和新型的靶向选择。
发明内容
通过提供在权利要求中表征的实施方式来实现所述目标的解决方案。
发明人发现了新的化合物，其是有用的放射药剂，以及它们在核医学中作为示踪物、显影剂的用途和用于治疗各种前列腺癌的疾病状态。
具有连接基区域中的结构改变的新型显影剂具有改善的肿瘤靶向性能和药代动力学。药效团呈现三个能够与PSMA的相应侧链相互作用的羧基以及作为活性中心中的锌络合(zinc complexation)的部分的氧。除了这些必须的相互作用，发明人能够优化连接基区域中的亲脂性相互作用。
附图说明
图1：MB17的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像(whole-body coronal microPET image)。通过动态microPET扫描评估[68Ga]MB17的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。图A示出了肾脏和膀胱相应的时间-活性曲线，并且图B为心脏、肌肉和肿瘤相应的时间-活性曲线。数值表示为平均SUV(标准化吸收值)。
图2：注射后1h的器官分布
0.06nmol的68Ga标记的PSMA抑制物MB17注射后一小时的器官分布。通过共给予2mg/kg体重的2-PMPA的PSMA阻断表示在肿瘤和肾脏中的PSMA特异吸收。数据表示为平均％ID/g组织±SD(n＝3)。
图3：MB4的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB4的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。图A示出了肾脏和膀胱相应的时间-活性曲线，并且图B为心脏、肌肉和肿瘤相应的时间-活性曲线。数值表示为平均SUV(标准化吸收值)。
图4：0.06nmol的177Lu标记的MB17注射后24h表示为％ID/g组织±SD(n＝5)的器官 分布
177Lu的器官分布示出，较高的初始肾脏吸收在24小时之后接近完全洗出(2.13±1.36％ID/g)，而肿瘤吸收保持较高并且甚至增加(10.58±4.50％ID/g)。其他器官，如肝脏(0.08±0.03％ID/g)、肺(0.11±0.13％ID/g)和脾(0.13±0.05％ID/g)示出了非常低的吸收。有利的药物动力学导致24小时之后极高的肿瘤与背景比率(肿瘤/血液：1058；肿瘤/肌肉：529)。
图5：MB2的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB2的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图6：MB3的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB3的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图7：MB10的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB10的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图8：MB:17.D的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB17.D的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
MB17D：MB17(L)的立体异构体；基于Fmoc-3(2-萘基)-D-甘氨酸合成
图9：MB22的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB22的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图10：MB24的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB24的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图11：MB25的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB25的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图12：MB31的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB31的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图13：MB33的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB33的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图14：MB35的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB35的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图15：用68Ga-CHX-DTPA注射的小鼠的PET扫描
左侧为尾侧视图(caudal)，中间为背侧视图(dorsal)并且右侧为侧面视图(lateral)。该图片覆盖20-40分钟(顶部)、40-60分钟(中间)和120-140分钟(底部)的时间间隔。
图16：MB-17相对于MB-17.D
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。在注射后2小时直接比较立体异构体MB-17和MB-17D的肿瘤靶向疗效和药代动力学性能。
图17：68Ga标记MB17的人类PET/CT成像
(a)具有68Ga标记的MB17PET/CT的第一临床经验表明在注射后1小时检测到小淋巴结的转移，主要是由于较高的放射示踪物吸收。红色箭头指向注射后一小时具有36.5的最大SUV和52.1的肿瘤与背景比率的代表性病灶。MIP＝注射后1h PET的最大密度投影。
(b)68Ga标记的MB17PET/CT的显著优势是即使在低PSA水平下对病灶灵敏的探测。
图18：具有多重前列腺癌转移(multiple prostate cancer metastasis)的患者 的PET成像
(a)第一扫描显示了具有14的血液PSA值的，具有多重前列腺癌转移的患者的初始PET成像。两个月后施加3.3GBq的177Lu标记的MB17。在此时间点，血液中的PSA量达到38的值。在第一循环(cycle)后，PSA水平降至8。在第一循环后三个月施加另外4GBq的177Lu标记的MB17。在第二循环后一个月进行对照PET扫描(control PET scan)。该疗法示出对肿瘤病灶(lesion)和PSA值的显著影响并导致骨痛的减少。
(b)该图表明对PSA值的显著影响，其在首次施加治疗剂量的177Lu标记的MB17之后降低。
具体实施方式
本发明涉及放射药剂和它们在核医学中作为示踪物、显影剂的用途和用于治疗各种前列腺癌的疾病状态。
因此，本发明涉及由通式(1a)或(1b)表示的化合物：
式(1a)
或
式(1b)
其中：
如果不另外说明，在本发明中“烷基”残基(优选地：C1至C10)可以是线性的或支链的，未取代的或取代的。优选的烷基残基是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基。同样也适用于优选地具有3至10个碳原子的相应环烷基化合物。
“芳基”是指具有6至14个碳原子，优选地6至10个碳原子的芳香族单环或多环的环系统。芳基基团可以是适当地由一个或多个环取代基，如烷基基团取代的。优选的芳基基团是苯基、苄基或萘基。
虽然Z-基团是-CO2H是优选的，其可以容易地由生物异构体替换物替换，如-SO2H、-SO3H、-SO4H、-PO2H、-PO3H、-PO4H2，见，例如“The Practice of Medicinal Chemistry”(Academic Press New York，1996)，203页。
在本发明的含义内，认为所有残基是可结合的，除非在残基的定义中另有说明。其所有可以想到的子群(subgrouping)被认为是公开的。
在优选的实施方式中，特异地结合至赘生性细胞(neoplastic cell)的细胞膜的基序是特异地结合癌性细胞的细胞膜的基序，优选地，其中所述基序包含前列腺特异性膜抗原(PSMA)，具体地，其中所述PSMA包含根据方案1中的下式的谷氨酸-脲-赖氨酸基序。
因此，本发明的优选的分子由三种主要组分组成(方案1)：亲水PSMA结合基序(Glu-脲-Lys；＝Glu-NH-CO-NH-Lys)、可变的连接基和优选地是DOTA的螯合剂。
方案1：本发明优选的化合物的结构
以下示出不同的优选的连接基，其中R＝Glu-脲-Lys并且R'＝DOTA(作为螯合剂的优选实例)，如以上示出。
MB2连接基
化学式：C36H54N8O15
分子量：838,88g/mol
MB3连接基
化学式：Ο44Η61N9O16
分子量：972,03g/mol
MB4连接基
化学式：C52H68N10O17
分子量：1105,18g/mol
MB10连接基
化学式：C65H70N11O8
分子量：1238,33g/mol
MB17连接基
化学式：C49H71N9O16
分子量：1042,16g/mol
MB22连接基
化学式：C36H60N8O15
分子量：844,92g/mol
本发明优选的化合物例如
本发明还涉及通式(1a)和/或(1b)的化合物的药学上可接受的盐。本发明还涉及，化合物的溶剂化物，包括其盐和活性代谢物，以及，适当的，包括前体药物制剂的根据通式(1a)和/或(1b)的它们的互变异构体。
“药学上可接受的盐”是本发明的化合物的药学上可接受的，有机或无机酸或碱的盐。代表性的药学上可接受的盐包括，例如碱金属盐、碱土盐、铵盐、可溶于水的和不可溶于水的盐，如乙酸盐、碳酸盐、氯化物、葡萄糖酸盐、谷氨酸盐、乳酸盐、月桂酸盐、苹果酸盐或酒石酸盐。
术语“前体药物”是指药物的前体，其是当给予患者时，在变为活性药理学试剂之前必须经受由代谢过程的化学转化的化合物。示例性的根据式(1a)和/或(1b)的化合物的前体药物是酯和酰胺，优选地脂肪酸酯的烷基酯。此处前体药物制剂包含所有的由酶、代谢或任何其他方式的简单转化，包括水解、氧化或还原形成的物质。适合的前体药物含有，例如通式(1a)和/或(1b)通过可酶剪切的连接基(例如氨基甲酸酯、磷酸酯、N-葡萄糖苷或二硫基团)结合至溶解性改善物质(例如四乙二醇、糖类、甲酸或葡糖醛酸等)的物质。可以将这样的根据本发明的化合物的前体药物施加于患者，并且该前体药物可以转变为通式(1a)和/或(1b)的物质以获得期望的药理学效果。
以消旋体、它们的对映异构体的形式，和可选地以它们的非对应异构体及其所有可能的混合物的形式包含一些式(1a)和/或(1b)的化合物。
根据本发明，所有的手性C原子应当具有D-和/或L-构型；在一个化合物内的组合也应该是可能的，即一些手性C原子可以是D-并且其他可以是L-构型。
可以可选地通过已知的方法(例如Allinger,N.L.und Elliel E.L.in“Topics inStereochemistry”Vol.6，Wiley Interscience，1971)将获得的化合物分离为它们的对映异构体和/或非对映异构体。一种可能的对映异构分离方法是使用层析。
本发明还涉及含有治疗有效量的活性成分(根据本发明的式(1a)或(1b)的化合物)连同有机或无机固体或液体的，适于预期的给予，且与活性成分相互作用而没有缺点的药学上可接受的载体的药物制剂。
在本文中采用的词组“药学上可接受的”是指在合理的医学判断范围内，适合用于与患者的组织接触而没有过多的毒性、刺激、过敏反应、或其他问题或并发症，与合理的益处/风险比例相当的那些化合物、材料、组合物和/或剂型。
“患者”包括动物，如人类、猴子、奶牛、马、猫或狗。动物可以是哺乳动物如非灵长类和灵长类(例如猴子和人类)。在一个实施方式中，患者是人类。
通常，式(1a)或(1b)的化合物或其药物组合物可以口服或通过非肠道途径，通常注射或输液给予。
“非肠道给予途径”是指除肠和局部给予之外的给予模式，通常通过注射，并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内的注射和输液。
根据本发明的化合物的剂量是通过医师基于患者特定的参数，如年龄重量、性别、疾病的严重度等确定的。剂量优选地为0.00001mg/kg至100mg/kg体重，优选地0.001至50mg/kg体重并且最优选地0.01至10mg/kg体重。
对应于给予的种类，适当地配制药剂，例如以溶液或悬浮液、简单片剂或糖衣丸、硬或软胶囊、栓剂、卵状小体(ovule)、用于注射的制剂的形式，其是根据常用的医学方法制备的。
根据本发明的化合物可以适当的地连同另外的活性物质以及与药物组合物中常用的赋形剂和载体配制，例如(取决于要生产的制剂)滑石、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、可可脂、含水和非水载体、动物或植物来源的脂肪体、石蜡衍生物、乙二醇(特别是聚乙二醇)、各种增塑剂、分散剂或乳化剂、药学上相容的气体(例如空气、氧气、二氧化碳等)、防腐剂。
为了生产液体制剂，可以使用添加剂如氯化钠溶液、乙醇、山梨醇、丙三醇、橄榄油、扁桃仁油、丙二醇或乙二醇。
当使用用于输液或注射的溶液时，它们优选地是含水溶液或悬浮液，可以在使用之前生产它们，例如由冻干制剂，其含有这样的活性物质或连同载体，如甘露醇、乳糖、葡萄糖、白蛋白等。杀菌已经制成的溶液并且适当地与赋形剂，例如与防腐剂、稳定剂、乳化剂、增溶剂、缓冲剂和/或用于调节渗透压的盐混合。可以通过使用具有，组合物可以根据其适当地冻干的较小孔径的过滤器，无菌过滤来获得杀菌作用。还可以加入少量的抗生素以确保维持无菌。
如在本文中使用的短语“有效量”或“治疗有效量”意指包含本发明的化合物或其他活性成分(其对于在动物中的至少子群体的细胞中，以适合于任何医学处理的合理的益处/风险比例，有效地产生期望的疗效)的化合物、材料、或组合物的量。对于本发明的化合物的治疗有效量意指在疾病的预防治疗中提供治疗益处的单独的，或与其他疗法结合的治疗剂的量。与本发明的化合物联合使用，该术语可以包括改善总体疗法，减少或避免疾病的症状或起因，或增强治疗效能或与另一种治疗剂的协同作用的量。
如在本文中使用的术语“治疗(treating)”或“疗法(treatment)”旨在还包括诊断、防疫、预防、治疗法(therapy)和治愈(cure)。
术语“预防(prevent)”、“预防了(preventing)”、和“预防(prevention)”是指通过给予预防或治疗剂，预防患者疾病的发作、复发、或传播。
取决于发明的式(1a)和/或(1b)化合物用作放射性显影剂还是放射性药物，将不同的放射性核素络合至螯合剂。示例性的放射性核素包括，例如89Zr、44Sc、111In、90Y、66Ga、67Ga、68Ga、177Lu、99mTc、61Cu、62Cu、64Cu、67Cu、149Tb、152Tb、155Tb、161Tb、153Gd、155Gd、157Gd、213Bi、225Ac、230U、223Ra、165Er、和Fe。根据本发明的一个方面，放射性核素是111In、90Y、68Ga、64Cu、153Gd、155Gd、213Bi、225Ac、Fe、或177Lu。
如上所述，根据式(1a)或(1b)的化合物的络合物可以含有一种或多种适合用作放射性显影剂或治疗剂，用于治疗迅速增生的细胞，例如PSMA表达的前列腺癌细胞的放射性核素。根据本发明，将它们称为“金属络合物”或“放射性药物”。
优选的成像方法是正电子发射断层成像(PET)或单光子发射计算机断层成像(SPECT)。
因此，在一个实施方式中，提供包括络合物的药物组合物，该络合物包括放射性核素和式(1a)或式(1b)的化合物、其盐、溶剂化物、立体异构体或互变异构体、以及药学上可接受的载体。
根据另一方面，提供药物组合物，其适用于体内成像和放射疗法。适合的药物组合物可以含有放射性显影剂，或足以成像的量的，具有作为元素，即放射性碘，或式(1a)和/或(1b)的化合物的放射性金属螯合复合物的放射治疗剂，连同药学上可接受的放射学介质(vehicle)。放射学介质应当适用于注射或吸入，如人血清白蛋白；含水缓冲溶液，例如三(羟基甲基)氨基甲烷(及其盐)、磷酸盐、柠檬酸盐、碳酸氢盐等；无菌水、生理盐水；以及含有氯和/或碳酸氢盐，或正常血浆的阳离子如钙、钾、钠和镁的平衡的离子溶液。
显影剂或治疗剂在放射学介质中的浓度应足以提供符合要求的成像。例如，当使用含水溶液时，剂量为约1.0至100毫居里。然而，给予患者用于成像或治疗目的实际剂量是由给予治疗的医师确定的。应当给予显影剂或治疗剂以保持在患者中约1小时至10天，尽管更长和更短的时间段是可接受的。因此，可以制备含有1至10mL的含水溶液的方便的安瓿瓶。
可以以标准方式进行成像，例如通过注射足量的成像组合物以提供足够的成像，并且然后用适合的成像或扫描机，如断层成像或伽马相机进行扫描。在某些实施方式中，成像患者中的区域的方法包括以下步骤：(i)给予患者诊断有效量的络合有放射性核素的化合物；使患者的区域暴露至扫描设备；以及(ii)获得患者的区域的图像。在某些实施方式中，成像的区域是头部或胸部。在其他实施方式中，式(1a)和/或(1b)的化合物和络合物靶向PSMA蛋白质。
因此，在一些实施方式中，提供成像组织如脾脏组织、肾脏组织、或PSMA表达的肿瘤组织的方法，包括将组织与通过将放射性核素与式(1a)和/或式(1b)的化合物接触合成的络合物接触。
本发明的化合物，或包含金属与根据式(1a)和/或(1b)的化合物的络合物，或其盐、溶剂化物、立体异构体、或互变异构体的络合物的制剂(给予患者)的量取决于医师常规使用的多个生理学因素，包括进行成像的性质、靶向用于成像或治疗的组织以及使用放射药剂成像或治疗的患者的体重和病史。
因此在另一方面中，本发明提供通过将治疗有效量的式(1a)和/或(1b)的络合至放射性核素的化合物或该络合物的药学上可接受的盐或溶剂化物给予患者来治疗患者的方法，以治疗遭受细胞增生疾病或失调的患者。具体地，使用根据本发明的化合物、药物组合物或放射药剂治疗或成像的细胞增生疾病或失调是癌症，例如前列腺癌和/或在例如肺脏、肝脏、肾脏、骨、脑、脊髓、膀胱等中的前列腺癌转移。
在实施例部分中详细描述本发明的化合物的合成。在考虑DOTA连接的PSMA抑制剂的方案2中举例说明该合成的概况。然而，本领域技术人员能够通过，例如使用另一种螯合剂修改该反应。因此，该方案不应理解为将本发明的化合物仅限于DOTA螯合剂。
方案2
通过RP-HPLC、MS、和/或NMR化学表征合成的化合物。
具有连接基区域中的结构改变的新型螯合剂连接的显影剂具有改善的肿瘤靶向性能和药代动力学。药效团呈现为三个能够与PSMA的相应侧链相互作用的羧基以及作为活性中心中的锌络合的部分的氧。除了这些必须的相互作用，发明人能够优化连接基区域中的亲脂性相互作用。
临床前的评估包括体外试验(亲和性，内化)和体内实验(μPET筛选和器官分布)。
本发明的化合物在肾脏清除和肿瘤中富集方面优于已知的参考化合物。本发明的PSMA抑制剂的结合亲和性可以受连接基改变的影响。该物质中的连接基区域中的两个环状基序和至少一个芳香族部分看起来是优选的，并且导致高亲合性的MB4和MB17化合物。在这方面，非常有希望的化合物是MB17。
因此本发明的化合物代表了，具有也由器官分布和小动物PET成像确认的最佳特性的新型的PSMA靶向探针。本发明的化合物示出了高度的PSMA特异性肿瘤吸收。此外，它们特征在于膀胱中的早期富集以及最大的肾脏吸收。在治疗用途方面，其给出本发明的化合物相比其他的PSMA抑制剂的明显的临床优势。在PET图中，本发明的化合物，特别是MB17示出了迅速的背景清除以及2小时之后肾脏中富集的显著降低，同时其进一步聚集并保留在PSMA表达的肿瘤中。使用MB17的体内治疗也首先示出了有希望的数据(参见图17和18)。
以下的实施例更详细地说明本发明，但不应解释为以任何方式将本发明仅限制于举例说明的实施方式。
实施例
实施例1：DOTA-连接的抑制剂的合成
通过固相肽合成来合成DOTA连接的PSMA抑制剂(参见方案2)。在第一步骤中，通过在5℃下3h中将在200mL的干燥CH2Cl2中的3mmol的双(叔丁基)-L-谷氨酸盐酸盐和3mL的N-乙基二异丙胺(DIPEA)加入在10mL的干燥CH2Cl2中1mmol的三光气的溶液中原位生成谷氨酰基部分的异氰酸酯。在反应之后加入0.5mmol的树脂固定的(2-氯-三苯甲基树脂)ε-烯丙氧基羰基保护的赖氨酸并在缓和搅拌下反应16h。将树脂滤除并使用在4mL CH2Cl2中的50mg四(三苯基)钯和400μL吗啉在2h中移除烯丙氧基保护基团。
根据标准的Fmoc流程进行随后的拟肽PSMA结合基序的合成。使用在最终体积4mLDMF中的2mmol的相应的Fmoc保护的酸、3.96mmol的HBTU和2mmol的N-乙基-二异丙胺进行连接基部分的随后的连接。在用3.95eq的HBTU和DIPEA活化2h后，将相对于树脂负载4eq的三(叔丁基)-DOTA(CheMatech)在最终体积3mL的DMF中反应。将产物从在2mL由三氟乙酸、三异丙基硅烷、和水(95:2.5:2.5)组成的混合物中树脂上剪切。
还通过使用HBTU活化的DOTA-NHS酯(CheMatech)或DOTA-TFP酯连接螯合剂(MierW.,Hoffend J.,Kramer S.,Schuhmacher J.,Hull W.E.,Eisenhut M.,Haberkorn U.,Bioconjugate Chem.2005,16:237-240)。
使用具有线性A-B梯度(6分钟内从0％B至100％B)的反相高效液相色谱(RP-HPLC；Chromolith RP-18e，100×4.6mm；Merck，Darmstadt，Germany)以4mL/min(分析)或6mL/min(纯化)的流速进行合成分子的分析。溶剂A由0.1％的TFA水溶液组成并且溶剂B是在CH3CN中的0.1％的TFA。HPLC系统(L6200A；Merck-Hitachi，Darmstadt，Germany)配备有UV和伽马探测器(gamma detector)(Bioscan；Washington，USA)。在214nm下测量UV吸光度。用MALDI-MS Daltonics Microflex系统(Bruker Daltonics，Bremen，Germany)进行质谱分析。
实施例2：放射性标记
通常，将1.5nmol实施例1的合成化合物(溶解在0.1M的pH7.5的HEPES缓冲液中)以100μL的体积加入10μL的2.1M的HEPES溶液和40μL的[68Ga]Ga3+洗脱液(40MBq)的混合物。将标记溶液的pH调节至4.5。
化合物的放射性标记导致在95℃下15分钟之后>97％的放射性化学产率，并且由RP-HPLC和TLC测定。使用Sep-Pak C18夹座(cartridge)完成随后的纯化。
实施例3：化合物MB4和MB17的合成
通过在0℃下在4h中，将在200mL干燥CH2Cl2中3mmol的双(叔丁基)L-谷氨酸盐酸盐和1.5mL的N-乙基二异丙胺(DIPEA)的混合物加入在10mL干燥CH2Cl2中1mmol三光气的溶液，原位生成谷氨酰基部分的异氰酸酯。在将反应混合物在25℃下搅拌1h之后，加入在4mL DCM中的0.5mmol的树脂固定的(2-氯-三苯甲基树脂)ε-烯丙氧基羰基保护的赖氨酸并在缓和搅拌下反应16h。将树脂滤除并使用在4mL CH2Cl2中的30mg四(三苯基)钯(0)和400μL吗啉在3h中移除烯丙氧基保护基团。随后三次连接4-(Fmoc-氨甲基)苯甲酸(MB4的情况)或Fmoc-3-(2-萘基)-L-甘氨酸和反式-4-(Fmoc-氨甲基)环己烷羧酸(MB17的情况)，分别是使用在4mL最终体积的DMF中的2mmol的Fmoc保护的酸、1.96mmol的HBTU和2mmol的N-乙基二异丙胺逐步进行的。在用3.95eq的HBTU和DIPEA活化2h后，将相对于树脂负载4eq的三(叔丁基)-DOTA(Chematech)在最终体积3mL的DMF中反应3h。将产物从在2mL由三氟乙酸、三异丙基硅烷、和水(95:2.5:2.5)组成的混合物中的树脂上剪切。使用RP-HPLC进行纯化并通过分析型RP-HPLC和MALDI-MS分析纯化的产物。
为制备作为MB17(L)的立体异构体的MB-17D，基于Fmoc-3(2-萘基)-D-甘氨酸合成。如果不另外说明，在本说明书中MB-17意指L-立体异构体。
实施例4：连接至各种螯合剂
通过固相合成将螯合剂(DOTA、NOTA、NODAGA、DTPA、CHX-DTPA、PCTA、Do3A)连接至MB17连接基。通常，将13μmol的与PSMA结合基序连接的树脂在带有过滤器的注射器中用DCM溶胀。在用DMF洗涤树脂5次之后，将其用在DMF中的20％的哌啶温育5分钟2次以将N-末端去保护。随后用DMF另外洗涤5次。
将1.5和4当量之间的螯合剂(取决于螯合剂)、0.98×n螯合剂HATU(如果需要的话)和10当量的DIPEA溶解在500μl的DMF中，将溶液吸入含有树脂的注射器中并温育过夜。然后，将树脂用DMF、甲醇、DCM和二乙醚各洗涤5次并在真空中干燥。
使用测试分离物以检查反应的状态。这是通过将少量树脂用DCM洗入过滤器尖端(filter tip)并加入含有95％的TFA、2.5％的水和2.5％的TIPS的100μl的分离溶液实现的。在温育30分钟之后，将溶液吸移入冰冷的二乙醚中并离心。将二乙醚倾析并将残余的颗粒溶解在35μl的ACN:H2O(1:1)中，并通过HPLC(5分钟内在水中0-100％ACN)和LC/MS分析。
如果获得期望的产物，将完全的肽(complete peptide)与树脂分离。将干燥的树脂用500μl的分离溶液(95％TFA、25％H2O、2.5％TIPS)温育2小时。将得到的溶液与用冰冷的二乙醚混合并离心(4000min-1，5分钟)。弃去上层清液，加入新的二乙醚并剧烈摇晃容器以再悬浮颗粒。再次，将溶液离心(4000min-1，5分钟)并弃去得到的上层清液。然后真空干燥颗粒并最终再悬浮在1mL的ACN:H2O(1:1)中。
通过制备型HPLC实现纯化，通过分析型HPLC(5分钟内在水中0-100％的ACN)和LC/MS分析峰并将含有产物的那些汇聚(pool)并冻干。
实施例5：放射性标记
177Lu标记
将177Lu(大约100MBq)与200μl的含有Chelex的0.4M醋酸钠缓冲液(pH＝5)混合。将10μl的在水中的10％DMSO中的该化合物的1mM溶液、2μl的抗坏血酸的饱和溶液和40μl的含有177Lu的溶液混合并加热至95℃10分钟。通过放射HPLC(5分钟内，在水中0-100％ACN，Monolith柱)检查标记。
68Ga标记
对于PET扫描，用68Ga标记CHX-DTPA。用0.6M的HCl从68Ge/68Ga生成器中洗脱1ml的68Ga。加入298μl的NaOAc缓冲液和1μl的在DMSO中的10mM CHX-DTPA溶液并温育5分钟。然后使用SOLA夹座纯化产物。使用0.9％的NaCl溶液完成洗涤并使用乙醇洗脱。然后将乙醇蒸发并将剩余的产物溶解在100μl的0.9％的NaCl溶液和10μl的磷酸盐缓冲液中。
实施例6：IC50值的测定
在室温下用100μl的PBS，用每孔1％的BSA温育滤板MultiScreenHTS-DV 30分钟。在移除PBS/BSA之后将在50μl的Opti-MEM中105LNCaP细胞的溶液施加于每个孔。将在300μl的Opti-MEM中不同浓度的化合物(导致每孔中0、0.5、1、2.5、5、10、25、50、100、500、1000和5000nM浓度)与3μl的在Opti-MEM中的150nM的125I标记的MIP-1466的溶液混合。将50μl得到的溶液加入每个孔中，将每个浓度一式四份地(in quadruples)吸移。现在每个孔含有0.75nM浓度的放射性标记的配体，以及上述浓度的竞争性未标记配体。然后将板在室温下在摇床上温育45分钟。
温育之后，将细胞用100μl冰冷的PBS洗涤2次并用200μl冰冷的PBS洗涤1次。最终，收集过滤器并用伽马计数器(gamma counter)测量剩余的放射性。每个管测量5分钟。
用Graphpad Prism评估由伽马计数器测量的数据以得到针对放射性标记的MIP-1095的抑制浓度50(IC50)。
连接物 IC50[nM]
MB17-DOTA 0.13±0.08
MB17-NOTA 0.14±0.08
MB17-DTPA 0.12±0.05
MB17-CHX-DTPA 0.06±0.04
MB17-PCTA 0.10±0.06
MB17-DO3A 0.10±0.05
MB17-NODAGA 0.09±0.08
实施例7：使用CHX-DTPA-MB17的μPET成像
在注射入小鼠之前，将含有纯化的68Ga-CHX-DTPA连接的PSMA抑制剂的溶液无菌过滤。将100μl的该溶液吸入注射器并且然后注射入BALB/c裸鼠的LNCaP异种移植，静脉内注入尾部静脉。用Siemens Inveon PET记录PET扫描140分钟(图15)。
实施例8：竞争性结合亲合性的测定
为比较新型化合物的系列，使用PSMA表达的细胞系LNCaP分析竞争性结合亲合性和特异性内化。为确定特异性细胞吸收，用2-(膦酰基甲基)-戊二酸(PMPA)阻断细胞。还通过基于酶的NAALADase试验研究抑制效力。
细胞培养
对于结合研究和体内实验，将LNCaP细胞(人类前列腺腺癌的转移性病灶，ATCCCRL-1740)在补充有10％胎牛血清和Glutamax(PAA，奥地利)的RPMI介质中培养。在细胞培养过程中，细胞在37℃下在具有加湿空气的，用5％的CO2平衡的恒温箱器中生长。使用胰蛋白酶-乙二胺四乙酸(胰蛋白酶-EDTA；0.25％胰蛋白酶，0.02％EDTA，均来自PAA，奥地利)收获细胞并用PBS洗涤。
细胞结合和内化
如先前描述的进行竞争性细胞结合试验和内化(internalization)实验(Eder etal.2012)。简要地，将相应的细胞(105每孔)用放射性配体(68Ga标记的[Glu-脲-Lys(Ahx)]2-HBED-CC)在12种不同浓度的分析物(0-5000nM，100μL/孔)的存在下温育(Schafer etal.,2012)。温育后，使用多滤网真空歧管(multiscreen vacuum manifold)(Millipore，Billerica，MA)进行洗涤。使用伽马计数器(Packard Cobra II，GMI，Minnesota，USA)测量细胞结合放射性。通过使用非线性回归算法(Graphpad软件)拟合数据来计算50％抑制浓度(IC50)。实验进行三次。
为测定特异性细胞吸收和内化，在温育之前24h将105细胞种在聚-L-赖氨酸涂覆的24孔细胞培养板中。洗涤后，将细胞用25nM的放射性标记化合物分别在37℃和4℃下温育45分钟。通过用2-(膦酰基甲基)戊二酸(500μΜ最终浓度，PMPA，Axxora，Loerrach，Germany)的竞争性阻断测定特异性细胞吸收。通过用1mL的冰冷的PBS洗涤4次来终止细胞吸收。随后将细胞用在PBS中0.5mL的甘氨酸-HCl(50mM，pH＝2.8)温育5分钟两次以去除表面结合的部分。用1mL的用冰冷的PBS洗涤细胞并使用0.3N NaOH(0.5mL)溶解。在伽马计数器中测量表面结合的和内化的部分。细胞吸收计算为结合至106细胞的初始加入的放射性的百分比[％ID/106细胞]。
Naaladase试验
将重组体人类PSMA(rhPSMA，R&D systems，Wiesbaden，Germany)在试验缓冲液(50mM HEPES，0.1M NaCl，pH 7.5)中稀释至0.4μg/mL。在最终体积125μL的试验缓冲液中，以0.05nM至1000nM范围的浓度将底物Ac-Asp-Glu(Sigma，Taufkirchen，Germany，40μΜ最终浓度)与natGa标记的分析物混合。将混合物与125μL的rhPSMA溶液(0.4μg/mL)结合并在37℃下温育一小时。通过在95℃下加热5分钟来停止反应。将250μL的15mM的邻-邻苯二甲醛(Sigma，Taufkirchen，Germany)溶液加入所有的小管中并在室温下温育10分钟。最后，将200μL的反应溶液加载在F16Black Maxisorp Plate(Nunc，Langenselbold，Germany)上并分别在330nm和450nm的激发和发射波长下使用酶标仪(microplate reader)(DTX-880，Beckman Coulter，Krefeld，Germany)读数。通过Graphpad(Graphpad Software，California，USA)的一点-总结合回归算法分析数据。
生物分布
将7至8周大的雄性BALB/c nu/nu小鼠(Charles River Laboratories)用5×106细胞的LNCaP(在50％基质胶中，Becton Dickinson，Heidelberg，Germany)皮下接种入右侧躯干。使得肿瘤生长直至约1cm3的尺寸。将放射性标记化合物注射入尾部静脉(约1MBq/鼠；0.06nmol)。在注射后1h杀死动物。将感兴趣的器官解剖、吸干(blot dry)、并称重。使用伽马计数器测量放射性并计算为％ID/g。
MicroPET
将10-25MBq的放射性标记化合物以0.15mL的体积(～0.5nmol)通过侧尾部静脉注射入带有LNCaP肿瘤异种移植的小鼠，用于microPET研究。将麻醉的动物(2％七氟醚(sevoflurane)，Abbott，Wiesbaden，Germany)以卧姿(prone position)放入Inveon小动物PET扫描仪(Siemens，Knoxville，Tenn，USA)以进行动态microPET扫描和20分钟静态扫描，参见图1、3、5-14。
表A
本实施例示出，PSMA抑制剂的结合亲和度可以受连接基改变的影响。该物质中的连接基区域中的两个环状基序和至少一个芳香族部分看起来是优选的，并且导致高亲合性的MB4和MB17化合物。这些新型的变体示出了对LNCaP细胞系的低纳摩尔亲合性，并且具体地在37℃下内化最多达48％ID/106细胞。先前的研究示出，除结合亲合性外，PSMA靶向探针的内化性能也是高度重要的，并且高内化速率对于高体内肿瘤吸收和存留是必要的。因此MB17代表了，具有也由器官分布和小动物PET成像确认的最佳特性的新型的PSMA靶向探针。MB17示出了较高的PSMA特异性肿瘤吸收(图2)。此外MB17的动态PET成像(图2)示出了膀胱中的早期富集并且最大的肾脏吸收(时间-活性曲线的最高点)早在放射示踪物注射后15分钟，且基本上在20分钟后已经减少。在治疗用途方面，其给出MB17相比其他的PSMA抑制剂的明显的临床优势。在PET图(图1)中，MB17示出了迅速的背景清除以及2小时之后肾脏中富集的显著降低，同时其进一步聚集并保留在PSMA表达的肿瘤中。
此外，177Lu的器官分布(图4)示出，24小时之后较高的初始肾脏吸收接近完全洗出(2.13±1.36％ID/g)，而肿瘤吸收保持较高并且甚至增加(10.58±4.50％ID/g)。其他器官，如肝脏(0.08±0.03％ID/g)、肺脏(0.11±0.13％ID/g)和脾脏(0.13±0.05％ID/g)示出了非常低的吸收。有利的药代动力学导致24小时之后极高的肿瘤与背景比率(肿瘤/血液：1058；肿瘤/肌肉：529)。
表A清楚地确定，分子的连接基区域的化学改变影响了生物学性质，例如亲合性和内化疗效。MB17和MB4示出了最有希望的细胞结合性。
实施例9：关于MB17的临床数据
使用用Ga-68标记的放射示踪物MB17进行PET/CT成像(参见图17)。
用于产生放射药剂的68Ge/68Ga生成器购自IDB-Holland BV(Baarle-Nassau，TheNetherlands)。用于放射合成的，包括GMP兼容等级的前体的一次性卡座试剂盒和化学品获得自ABX advanced biochemical compounds(Radeberg，Germany)。配备有ChromolithPerformance RP-18e柱(100×4.6mm，Merck)和Nal放射探测器(Raytest)的Ultimate3000HPLC系统(Dionex)(乙腈(A)、水+0.1％TFA(B)；梯度：0.5分钟95％B、10.0分钟80％A，流速：2mL/分钟)用于测定放射化学品纯度。使用6850系列气相色谱仪(AgilentTechnologies)测定残留溶剂。用设备(Charles River)进行内毒素测试。
将2μg的MB17溶解在1.5M的pH 4.5的乙酸盐缓冲液(1mL)和1M的抗坏血酸(10μL)中并移入反应容器。用10mL的0.6M HCl洗脱68Ge/68Ga生成器并用9mL的超纯水稀释洗出液。然后将混合物移至阳离子卡座(cartridge)(Macherey-Nagel PS-H+，尺寸M)并用5M的NaCl溶液(1.2mL)洗脱入预热的反应容器中(100℃)。加热反应混合物10分钟。然后将粗反应混合物移出反应容器并移至预处理的(10mL EtOH/10mL超纯水)C18卡座(Waters Sep-Paklight)。使用9mL超纯水冲洗反应容器并经过C18卡座。用另外5mL的超纯水洗涤C18卡座。用2mL的EtOH/H2O(v:v 1:1)从C18卡座洗脱最终产物，无菌过滤(Millipore Cathivex-GV，0.22μm)并用10mL的pH 7.4的磷酸盐缓冲盐水(PBS)溶液稀释(根据欧洲药典8.0(4005000))。将68Ga-MB17络合物溶液通过静脉推注(intravenous bolus)施加于患者。
实施例10：使用177Lu标记的MB17的人类治疗
用Lu-177放射性标记PSMA配体MB17，用于治疗。177LuCl3获得自Perkin Elmer(4GBq，NEZ307D，0,04M HCl)。将80纳摩尔的MB17溶解在补充有5μL的20％抗坏血酸的400μL醋酸钠缓冲液中。将溶液移至177LuCl3，并在95℃下温育10分钟。最后加入2mL 0.9％的NaCl。为了质量控制进行ITLC和放射HPLC。
将177Lu标记的MB17通过静脉推注(5mL，30秒内，缓慢)施加于患者。该静脉内施加伴有注射之前0.5h开始的4.5h的0.9％NaCl的输液。参考图18。

Claims (10)

1.一种式(Ia)或(Ib)的化合物：
(Ia)
或
(Ib)
其中
2.根据权利要求1所述的化合物，具有结构R'-连接基-R，其中R'＝DOTA且R＝Glu-脲-Lys：
其中，所述连接基选自
3.根据权利要求1或2所述的化合物，选自以下：
4.根据权利要求1至3中任一项所述的化合物用于制备放射性标记化合物的用途。
5.一种金属络合物，包含放射性核素和根据权利要求1至3中任一项所述的化合物。
6.根据权利要求5所述的金属络合物，其中，所述放射性核素是111In、90Y、68Ga、177Lu、99mTc、64Cu、153Gd、155Gd、157Gd、213Bi、225Ac或Fe。
7.一种药物组合物，包含根据权利要求1至3中任一项所述的化合物，或根据权利要求5或6所述的金属络合物，或其药学上可接受的盐或酯，以及药学上可接受的载体。
8.权利要求1至3中任一项所述的化合物或权利要求5或6所述的金属络合物在制备用于在患者中成像的药剂中的应用。
9.权利要求1至3中任一项所述的化合物或权利要求5或6所述的金属络合物在制备用于诊断前列腺癌和/或其转移的药剂中的应用。
10.权利要求1至3中任一项所述的化合物或权利要求5或6所述的金属络合物在制备用于治疗前列腺癌和/或其转移的药剂中的应用。
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