CN107847618A - Hbed‑二膦酸盐/酯、其放射金属轭合物和它们作为治疗诊断剂的用途 - Google Patents
Hbed‑二膦酸盐/酯、其放射金属轭合物和它们作为治疗诊断剂的用途 Download PDFInfo
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- CN107847618A CN107847618A CN201680046397.5A CN201680046397A CN107847618A CN 107847618 A CN107847618 A CN 107847618A CN 201680046397 A CN201680046397 A CN 201680046397A CN 107847618 A CN107847618 A CN 107847618A
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- bone
- hydrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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Abstract
本发明涉及根据式I或式II的化合物,其是用于治疗骨肿瘤和转移的潜在骨成像剂和治疗剂。用68Ga标记的某些化合物显示优异的骨摄取和保留。本发明也涉及药物组合物,其包含药物可接受的载体和式I或式II的化合物或其药学上可接受的盐。
Description
发明背景
[99mTc]-二膦酸亚甲基酯(MDP)平面或单光子发射计算机化断层摄影(SPECT)骨成像是最通常进行的核医学程序之一,其用于评价骨障碍比如感染(骨髓炎)、非传染性炎症(关节炎)、创伤、代谢性骨病、良性和恶性瘤和转移。仍然一直存在99mTc短缺的顾虑,其可以限制该成像剂用于常规临床用途的可获得性。最近,[18F]NaF与PET结合已被批准用于临床评价患者的已知或疑似骨转移。Iagaru A,et al.,Clin.Nucl.Med.38:e290-6(2013);Jadvar H,et al.,Semin.Nucl.Med.45:58-65(2015)。PET放射性示踪剂的地区商业分销中心日益增加,从而改善[18F]NaF(t1/2110分钟,97%β+,0.63MeV最高能量)用于常规临床实践的可获得性。
用于PET成像的68Ge/68Ga发生器在核医学诊所中正在变得可获得。Velikyan I.,J.Label.Compd.Radiopharm.DOI:10.1002/jlcr.3250(2015年2月17日在线公开)。存在与使用68Ga有关的数种优势:1)长寿命母体同位素锗-68(68Ge)(t1/2 271d)允许容易且广泛的发生器分布;2)68Ga的物理特性(t1/2 68分钟,89%β+,1.90MeV最高能量)高度适于PET成像;3)68Ge/68Ga发生器提供放射性同位素原位产生的方便机制,而不需要邻近的回旋加速器。需考虑的重要因素是18F和68Ga的发射β+能量分别是0.63MeV和1.90MeV。然而尽管β+能量有差异,18F和68Ga放射药剂展示相似的空间分辨率、敏感性、图像对比度和在人组织中的活性回收系数,并且它们在人中产生可比拟的临床图像。
由于68Ga相对短的物理半衰期及其用于结合至血液组分转铁蛋白的潜力,其用于68Ga放射药剂需要数种必需特性:1)68Ga配合物应显示高体外稳定性;2)68Ga配合物的形成应在动力学上快速;3)68Ga配合物应能够形成靶向、预轭合至生物学活性分子的双官能分子;和4)68Ga配合物应在血液循环中显示适宜的体内稳定性,具有最低的转铁蛋白交换。
目前,最常见的68Ga标记放射药剂经评价是[68Ga]DOTATOC,[68Ga]DOTATATE和[68Ga]DOTANOC。这些化合物主要用于检测与神经内分泌肿瘤有关的生长抑素受体的过表达。这吸引了将PET成像用于诊断神经内分泌肿瘤和各种疾病的显著注意力。Morgat C.etal.,Gallium-68:chemistry and radiolabeled peptides exploring differentoncogenic pathways,Cancer Biother.Radiopharm.28:85-97(2013);Sandstrom M,etal.J.Nucl.Med.54:1755-9(2013);Velikyan I,et al.,Quantitative and qualitativeintrapatient comparison of68Ga-DOTATOC and 68Ga-DOTATATE:net uptake rate foraccurate quantification,J.Nucl.Med.55:204-10(2014)。
许多Ga配合物已有报告,并且它们通常是大环或无环的多氮杂羧酸。这些配合物常常包括金属-螯合配体,其设计用来形成钆(Gd)配合物以用作磁共振成像(MRI)造影剂,比如:二亚乙基三胺五乙酸(DTPA),1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA),1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)和有关的衍生物(表1)。这些配体中有许多通常用来螯合放射性金属离子。它们包括用于SPECT成像的单光子放射同位素-67Ga,99mTc和111In,以及用于PET成像的正电子放射同位素-64Cu,86Y,89Zr,68Ga和89Sr。关于多氮杂羧酸比如DOTA和有关配体的文献报告所表明的是,它们与Ga(III)形成高度热力学稳定的配合物。但是,不加载体的(n.c.a.)68Ga与DOTA衍生物的配合已显示是效率低下的,常常需要80-100℃的加热。与NOTA类似物相比,DOTA配体与Ga(III)的形成对实验条件更敏感。可能的是,NOTA衍生物构成的更小空腔更紧密地贴合Ga(III)的离子半径。NOTA衍生物,特别是1-(1,3-羧基丙基)-4,7-羧甲基-1,4,7-三氮杂环壬烷(NODAGA),经显示比DOTA衍生物更适于螯合Ga(III)离子。Price E.W.and Orvig C.,Chem.Soc.Rev.43:260-90(2014);Oxboel J.,et al.,Nucl.Med.Biol.41:259-67(2014)。Ga(III)NODAGA配合物展示显著更高的热力学稳定性以及快速的配合物动力学。由于Ga(III)是小离子且一般需要八面体配位层,Ga(III)NODAGA类似物提供最佳的体外和体内稳定性。有数个报告优先选择Ga(III)NODAGA在产生双官能成像剂中充当螯合基团。通过使用DOTA和NOTA衍生物,许多68Ga标记的二膦酸盐/酯得以制备和测试用于骨成像。据报告二膦酸盐DOTA衍生物,[68Ga]4-{[(二-膦酰基甲基)氨基甲酰基]甲基}-7,10-二-(羧基-甲基)-1,4,7,10-四氮杂环十二碳-1-基)-乙酸(BPAMD),在人中显示良好的骨摄取和保留。Fellner M.,et al.,Eur.J.Nucl.Med.Mol.Imaging 37:834(2010)。
表1描述据报告能够配合68Ga用于骨成像的二膦酸盐/酯的结构。这些包括亚乙基-二氨基-N,N,N′,N′-四-亚甲基-磷酸(EDTMP),(4-{[(二-膦酰基甲基)氨基甲酰基]甲基}-7,10-二-(羧基-甲基)-1,4,7,10-四氮杂环十二碳-1-基)-乙酸(BPAMD),(4-{[(二-膦酰基丙基)氨基甲酰基]甲基}-7,10-二-(羧甲基)-1,4,7,10-四氮杂环十二碳-1-基)-乙酸(BPAPD),四乙基-10-{[(2,2-二-膦酰基乙基)-羟基磷酰基]甲基}-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(BPPED或DO3ABP)),(4-{[(二-膦酰基丙基)氨基甲酰基]羟基甲基}-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA-BP),2,2'-(7-(((2,2-二膦酰基乙基)(羟基)磷酰基)甲基)-1,4,7-三氮杂环壬烷-1,4-二基)二乙酸(NO2APBP),4-{[(二-膦酰基丙基)氨基甲酰基]甲基}-1,4,7-三氮杂环壬烷-1,4-二乙酸(NOTAMBP),1,4,7-三氮杂环壬烷-N,Nne-1,三(二-膦酰基丙基)氨基甲酰基]甲基-亚甲基膦酸)酸(TRAP(NOTP)),和1,4,7-三氮杂环壬烷-1,4,7-三[亚甲基次膦酸](TRAP(MDP)3)。基于DOTA和NOTA的二膦酸盐/酯,68Ga标记的BPAMD和NO2APBP已成功在人中测试作为骨成像剂。
表1.能够配合68Ga用于骨成像的二膦酸盐/酯
报告用于配合Ga(III)的数种螯合基团:DOTA,1,4,7-三氮杂环壬烷-1,4-二[亚甲基(羟基甲基)次膦酸]-7-[亚甲基(2-羧乙基)次膦酸](TRAP(NOPO)),环己基-1,2-[[6-羧基-吡啶-2-基]-甲基氨基]乙烷(H2CHX DEDPA),和(5S,8S,22S,26S)-1-氨基-5,8-二苄基-4,7,10,19,24-五氧代-3,6,9,18,23,25-六氮杂二十八-22,26,28-三羧酸三氟乙酸盐(CHX-A”-DTPA-DUPA-Pep)。参见Simecek J.,et al.,Chem.Med.Chem.8:95-103(2013);Ramogida C.F.,et al.,Inorg.Chem.54:2017-31(2015);Baur B.,et al.,Pharmaceuticals(Basel)7:517-29(2014)。
前列腺特异性膜抗原(PSMA)是高度特异性的前列腺上皮细胞膜抗原。许多报告表明PSMA在各种肿瘤包括前列腺癌中高度表达。常常,PSMA表达在晚期癌和转移病中增加。在实体肿瘤中的多数新血管系统中,存在PSMA高表达,但并不是在普通血管系统中。这使得PSMA称为癌检测和治疗的适宜靶标。某些Ga-前列腺特异性膜抗原(PSMA)标签化的配合物在体外显示对表达PSMA的肿瘤模型的高亲和力结合和有效靶向。在癌患者中成像PSMA结合位点的两种研究试剂是[68Ga]Glu-NH-CO-NH-Lys(Ahx)-HBED-CC(单体),及其有关二聚体,[68Ga](Glu-NH-CO-NH-Lys(Ahx))2-HBED-CC。制备了两种配合物并且经报告显示高PSMA结合,如表2所示。Baur B.,et al.,Pharmaceuticals(Basel)7:517-29(2014);Schafer M.,et al.,EJNMMI Res 2:23(2012);Eder M.,et al.,Pharmaceuticals(Basel)7:779-96(2014);Eder M.,et al.,Bioconjug.Chem.23:688-97(2012)。尽管[68Ga]Glu-NH-CO-NH-Lys(Ahx)-HBED-CC(单体)和[68Ga](Glu-NH-CO-NH-Lys(Ahx))2-HBED-CC(二聚体)均展示可比拟的临床前数据,目前特选用于人类研究的PSMA/PET成像剂是单体。一般接受的是Glu-NH-CO-NH-Lys(Ahx)-提供与肿瘤细胞膜上的PSMA受体的高结合亲和力。
表2.
PSMA靶向成像剂的建议结构
[68Ga]Glu-NH-CO-NH-Lys(Ahx)-HBED-CC(单体)和[68Ga](Glu-NH-CO-NH-Lys(Ahx))2-HBED-CC(二聚体)。
迄今绝大多数临床研究已用[68Ga]Glu-NH-CO-NH-Lys(Ahx)-HBED-CC(单体)进行。使用HBED而不是通常使用的DOTA和NOTA充当螯合Ga(III)的配体具有某些优势。Ga(III)-DOTA和Ga(III)-NOTA配合物的稳定性常数(log Kd)有预先报告(log Kd=分别21.3和31.0)。与DOTA和NOTA相比,HBED螯合基团形成更牢固、更稳定的Ga(III)配合物:Ga(III)-HBED-CC报告的log Kd值是38.5。
一直需要这样的骨成像剂,其使用可获得的放射性核素,快速形成配合物,在体外和在体内稳定,并且不将放射性核素快速转移至血流中的转铁蛋白。
发明概要
本发明的一个方面是新的HBEB CC二膦酸盐/酯衍生物及其与金属放射性核素的配合物。
在一种实施方式中,公开涉及根据式I的化合物:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
n是1至8;
Y独立地是CH或N;
R1是氢或(C1-C6)烷基;
R2,R5和R8独立地是氢或羧酸保护基团;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R6是氢或(C1-C6)酰基;和
R7是天然或非天然氨基酸的α-位取代基,和
R9独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基,芳基烷基和杂芳基。
在又一实施方式中,公开涉及在式I化合物与金属M之间的配合物,其中M选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb和51Cr。
在又一实施方式中,公开涉及根据式II的化合物:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
其中n是1至8;
Y独立地是CH或N;
R1是氢或(C1-C6)烷基;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R5和R8独立地是氢或羧酸保护基团;
R6是(C1-C6)酰基;
R7是天然或非天然氨基酸的α-位取代基;
R8独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基,芳基烷基和杂芳基;和
M是选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb和51Cr的金属。
在又一实施方式中,公开涉及式I化合物其中X是X6与金属M之间的配合物。在一种实施方式中,M是44Sc,47Sc,90Y,97Ru,和177Lu;其余基团如对式I的定义,其中放射金属在X6(DOTA)部分配合。
本公开的又一实施方式涉及形成式I的化合物的放射性标记配合物的方法。
本公开的又一实施方式涉及检测方法,包括向受试者给予式I化合物的放射性标记配合物或向受试者给予式II配合物,并且此后使所述受试者或所述受试者的一部分成像。
本公开的又一实施方式涉及在受试者中治疗骨肿瘤的方法,包括向所述受试者给予式I化合物的放射性标记配合物,其中M是44Sc,47Sc,90Y,97Ru和177Lu。
附图描述
图1描述普通小鼠于iv注射[18F]NaF后60分钟的微PET图像的矢状、经轴和冠状切面。
图2描述普通小鼠于iv注射[68Ga]BPAMD后60分钟的微PET图像的矢状、经轴和冠状切面。
图3描述普通小鼠于iv注射[68Ga]1a后60分钟的微PET图像的矢状、经轴和冠状切面。
图4描述[68Ga]1g摄取入表达PSMA的LNCaP细胞中的时间过程(%摄取/孔)的图。
图5描述在37℃温育之后[68Ga]1g的细胞摄取(%摄取/孔)。PSMA阳性LNCaP细胞显示优异的摄取,而PSMA阴性PC3细胞显示无摄取。特异性PSMA抑制剂2-PMPA(2-(膦酰基甲基)戊烷-1,5-二酸)阻断向PSMA阳性LNCaP细胞的细胞摄取。(T:总摄取,B:2-PMPA的阻断)。
图6A-6F描述在注射[68Ga]1g之后的小鼠微PET图像(500μCi,注射后60分钟,15分钟扫描)。
发明详述
使用放射标记的二膦酸盐/酯例如68Ga来靶向骨转移的正电子发射断层摄影(PET)成像能够是有价值的工具,其用于癌症诊断和用于监测医学治疗。含有一个二膦酸盐/酯基团(1a)或两个二膦酸盐/酯基团(2和3)的一系列的68Ga标记的N,N′-二[2-羟基-5-(羧乙基)苄基]乙二胺-N,N′-二乙酸(HBED-CC)化合物得以制备(表3)。也制备额外的含有二膦酸盐/酯-HBED-CC的化合物,包括缀合的2-氨基葡萄糖(1b),甘氨酸(1c),丙氨酸(1d),天冬氨酸(1e),谷氨酸(1f),Glu-NH-CO-NH-Lys(Ahx)(1g)和DOTA(1h)。新HBED配体1a-h、2和3,在乙酸钠缓冲剂中与从可商购68Ge/68Ga发生器洗脱的[68Ga]GaCl3快速反应(pH 4,>95%标记,在室温下,5分钟内)从而分别形成[68Ga]1a-h,[68Ga]2和[68Ga]3。该标记条件避免需要进一步纯化。[68Ga]1a-h和[68Ga]2在i.v.注射之后在普通小鼠中的生物分布显示优异的骨摄取和保留,可与[18F]NaF比拟。然而,[68Ga]3显示高肝摄取和低骨局域化,因此其不再进一步研究。结果表明[68Ga]1a-h和[68Ga]2是适宜的人骨成像剂,充当目前特选骨成像剂[18F]NaF的备择对象。本发明化合物提供与PET结合的实际体内骨成像剂,而不需要邻近的回旋加速器。
公开的是一类HBED-CC化合物,含有二膦酸盐/酯[68Ga]1a-h,[68Ga]2和[68Ga]3,对其进行制备和测试。因此,该系列的新化合物含有两个独立组分。第一,HBED螯合基团与68Ga(III)形成稳定配合物;第二,附着在螯合基团末段的二膦酸盐/酯基团用于靶向和结合至活性骨表面的羟基磷灰石,类似[99mTc]MDP的膦酸盐/酯基团。
表3
68Ga标记的含有二膦酸盐/酯的HBED-CC衍生物的化学结构,[68Ga]1a-h,[68Ga]2和[68Ga]3,和已知的骨成像剂[68Ga]BPAMD
在一种实施方式中,公开涉及根据式I的化合物:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
n是1至8;
Y独立地是CH或N;
R1是氢或(C1-C6)烷基;
R2,R5和R8独立地是氢或羧酸保护基团;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R6是氢或(C1-C6)酰基;和
R7是天然或非天然氨基酸的α-位取代基,和
R8独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基,芳基烷基和杂芳基。在一种实施方式中R8是H,烷基,环烷基,杂环烷基,芳基,烷基芳基和杂芳基。在又一实施方式中,R8是H,烷基或芳基烷基。
在一个方面,X是X1,X2,X3,X4或X5之一。
在又一方面,X是X6。在一个方面,n是1。
在又一实施方式中,公开涉及在式I化合物与金属M之间的配合物,其中M选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb和51Cr。
在又一实施方式中,公开涉及根据式II的化合物:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
Y独立地是CH或N;
n是1至8;
R1是氢或(C1-C6)烷基;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R5和R8独立地是氢或羧酸保护基团;
R6是(C1-C6)酰基;
R7是天然或非天然氨基酸的α-位取代基;
R8独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基和杂芳基;和
M是选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb和51Cr的金属。
在一个方面,M是67Ga或68Ga。
在某些实施方式中,本发明化合物由通式I和II和随之而来的定义代表,其中A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR8-或-C(O)-替换。在又一实施方式中,A是包含C1-C10亚烷基的二价连接部分,其中至少一个碳原子任选用O,-NR8-或-C(O)-替换。在又一实施方式中,A是(CH2)m,其中m是0至6的整数。在又一实施方式中,A是CH2。二价A部分的有用实例包括-CH2-,-CH2CH2-,-CH2CH2CH2-,-OCH2-,-OCH2CH2-,-OCH2CH2CH2-,-NHCH2-,-NHCH2CH2-,-NHCH2CH2CH2-,-COCH2-,-COCH2CH2-和-COCH2CH2CH2-。
在某些实施方式中,本发明化合物由通式I和II和随之而来的定义代表,其中X选自:
在其它实施方式中,式I或式II的X是:
在某些实施方式中,式I或式II的X是X6和n是1。
在又一实施方式中,X是羧酸基团或其衍生物(X1)。在又一实施方式中,X含有氨基葡萄糖基团或其衍生物(X2)。在又一实施方式中,X含有氨基酸残余物或其衍生物(X3)。在又一实施方式中,X含有Glu-NH-CO-NH-Lys(Ahx)(X4)。在又一实施方式中,X含有二膦酸盐/酯基团(X5)。
有用的R7基团包括甘氨酸,天冬氨酸,谷氨酸和2-氨基葡萄糖。
有用的R5和R8基团包括甲基酯,叔丁基酯,苄基酯和烯丙基酯。
在一种实施方式中,X是X1至X5之一和放射性核素金属(M)是68Ga.在又一实施方式中,X是X6和放射金属是177Lu或90Y。
在一种实施方式中,公开涉及具有下述结构的化合物:
其中n是1至8。在一种实施方式中,n是1。
在一种实施方式中,公开涉及具有下述结构的化合物:
其中n是1至8。在一种实施方式中,n是1。
本发明也提供药物组合物,包含药物可接受的载体和式I或式II化合物或药学上可接受的盐。在某些实施方式中,药物组合物包含产生根据式I或其子式的化合物或盐所必需的反应前体与放射性标记前体的组合。
本发明提供试剂盒配制剂,其包含含有式I化合物或用于iv注射的药学上可接受的等渗溶液的无菌容器,和用于诊断成像(68Ga)和辐射治疗用途(177Lu和90Y)的指导书。
本发明也提供体内成像方法,包括将有效量的式II放射金属配合物给予至受试者,并且检测所述受试者中配合物的放射性谱。
本发明化合物可以给予的典型受试者是哺乳动物,特别是灵长类,尤其是人类。对于兽医学应用,各式各样的受试者都是适宜的,例如牲畜比如牛,绵羊,山羊,奶牛,猪等;家禽比如鸡,鸭,鹅,火鸡等;和驯养动物特别是宠物比如犬和猫。为了诊断或研究应用,各式各样的哺乳动物都是适宜的受试者,包括啮齿类(例如小鼠,大鼠,仓鼠),兔子,灵长类,和猪比如杂交猪等。额外地,为了体外应用比如体外诊断和研究应用,适于使用上述受试者的体液和细胞样品比如哺乳动物特别是灵长类比如人的血、尿或组织样品,或对兽医学应用所提及的动物的血、尿或组织样品。
按照本发明的一种有用放射药剂是正电子发射镓-68配合物,其在与68Ge/68Ga母/子放射性核素发生器系统结合使用的情况下将使得PET成像研究成为可能,避免与操作室内回旋加速器产生放射性核素有关的费用。
放射药剂配合物按照本申请方法用于骨成像。配合物配制成适于静脉内给药的水溶液,用标准技术准备肠胃外诊断。本申请配合物的水溶液能够例如借助通过可商购0.2微米滤器来灭菌。配合物一般静脉内给予,其量有效提供放射性核素配合物的骨浓度,所述骨浓度足以提供必要的光子(γ/正电子)通量用于组织成像。为了实现可接受的组织成像的本发明任意给定配合物的剂量水平取决于其特定生物分布和组织成像设备的敏感度。有效剂量水平能够通过常规实验确定。它们一般的范围是约1至约30毫居里。在配合物是用于骨PET成像的镓-68配合物的情况下,通过静脉内给药约1至约30毫居里的配合物能够获得适当的光子通量。
术语"氨基酸"如本文所用包括天然氨基酸和非天然氨基酸两者。天然氨基酸是指已知用于形成蛋白质基本组分的氨基酸,包括丙氨酸,精氨酸,天冬酰胺,天冬氨酸,半胱氨酸,胱氨酸,谷氨酰胺,谷氨酸,甘氨酸,组氨酸,羟脯氨酸,异亮氨酸,亮氨酸,赖氨酸,甲硫氨酸,鸟氨酸,苯丙氨酸,脯氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸,缬氨酸,及其组合。非天然氨基酸的实例包括:酪氨酸的非天然类似物;谷氨酰胺的非天然类似物;苯丙氨酸的非天然类似物;丝氨酸的非天然类似物;苏氨酸的非天然类似物;烷基、芳基、酰基、叠氮基、氰基、卤代、肼、酰肼、羟基、烯基、炔基、醚、硫醇、磺酰基、硒基、酯、硫代酸、硼酸盐/酯、取代硼酸盐/酯、磷酸、膦酰基、膦、杂环、烯酮、亚胺、醛、羟胺、酮基或氨基取代的氨基酸,或其任意组合;具有可光激活的交联剂的氨基酸;自旋标记的氨基酸;荧光氨基酸;具有新官能团的氨基酸;与又一分子共价或非共价相互作用的氨基酸;结合金属的氨基酸;含金属的氨基酸;放射性氨基酸;光笼(photocaged)和/或光可异构化的氨基酸;含有生物素或生物素类似物的氨基酸;糖基化的或碳水化合物修饰的氨基酸;含酮基的氨基酸;包含聚乙二醇或聚醚的氨基酸;重原子取代的氨基酸;化学可裂解的或光可裂解的氨基酸;具有延伸侧链的氨基酸;含毒性基团的氨基酸;糖取代的氨基酸,例如糖取代的丝氨酸等;碳连接的含糖氨基酸;氧化还原活性的氨基酸;含α-羟基的酸;含氨基硫代酸的氨基酸;α,α二取代的氨基酸;β-氨基酸;和除脯氨酸外的环状氨基酸。
术语"酰基"如本文所用是指下述结构:
其中R20是烷基,环烷基,芳基,(环烷基)烷基或芳基烷基,其中任一个是任选经取代的。酰基能够是例如C1-6烷基羰基(比如乙酰基),芳基羰基(比如苯甲酰基),乙酰丙酰基或新戊酰基。在又一实施方式中,酰基是苯甲酰基。
术语"烷基"如本文所用包括支化和直链的饱和脂族烃基,其具有指定的碳原子数。烷基的实例包括但不限于甲基,乙基,正丙基,异丙基,正丁基,仲丁基,叔丁基,正戊基和仲戊基。优选的烷基是C1-C10烷基。典型的C1-10烷基包括甲基,乙基,正丙基,正丁基,正戊基,正己基,正庚基,正辛基,正壬基和正癸基,异丙基,仲丁基,叔丁基,异丁基,异戊基,新戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,1,1-二甲基丙基,1,2-二甲基丙基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1-乙基丁基,2-乙基丁基,3-乙基丁基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-甲基己基,2-甲基己基,3-甲基己基,4-甲基己基,5-甲基己基,1,2-二甲基戊基,1,3-二甲基戊基,1,2-二甲基己基,1,3-二甲基己基,3,3-二甲基己基,1,2-二甲基庚基,1,3-二甲基庚基和3,3-二甲基庚基等。在一种实施方式中,有用烷基选自直链C1-6烷基和支化链C3-6烷基。典型的C1-6烷基包括甲基,乙基,丙基,异丙基,丁基,仲丁基,叔丁基,异丁基,戊基,3-戊基,己基等。在一种实施方式中,有用烷基选自直链C2-6烷基和支化链C3-6烷基。典型的C2-6烷基包括乙基,丙基,异丙基,丁基,仲丁基,叔丁基,异丁基,戊基,3-戊基,己基等。在一种实施方式中,有用烷基选自直链C1-4烷基和支化链C3-4烷基。典型的C1-4烷基包括甲基,乙基,丙基,异丙基,丁基,仲丁基,叔丁基和异丁基。
术语"环烷基"如本文所用包括具有指定碳原子数的饱和环基团,比如环丙基,环丁基,环戊基或环己基。环烷基一般具有3至约12个环成员。在一种实施方式中,环烷基具有一个或两个环。在又一实施方式中,环烷基是C3-C8环烷基。在又一实施方式中,环烷基是C3-7环烷基。在又一实施方式中,环烷基是C3-6环烷基。示范性环烷基包括环丙基,环丁基,环戊基,环己基,环庚基,环辛基,降莰烷基,十氢萘和金刚烷基。
术语"杂环烷基"如本文所用是指饱和杂环烷基。
术语"芳基"如本文所用包括C6-14芳基,特别是C6-10芳基。典型的C6-14芳基包括苯基,萘基,菲基,蒽基,茚基,薁基,联苯基,联苯撑基和芴基,更优选苯基,萘基和联苯基。
术语"杂芳基"或"杂芳族"如本文所用是指具有5至14个环原子的基团,其中6、10或14个π电子在环状阵列中共享,并且含有碳原子和1、2或3个氧、氮或硫杂原子,或者4个氮原子。在一种实施方式中,杂芳基是5-至10-元杂芳基。杂芳基的实例包括噻吩基,苯并[b]噻吩基,萘并[2,3-b]噻吩基,噻蒽基,呋喃基,苯并呋喃基,吡喃基,异苯并呋喃基,苯并噁唑基,色烯基,呫吨基,2H-吡咯基,吡咯基,咪唑基,吡唑基,吡啶基,吡嗪基,嘧啶基,哒嗪基,异吲哚基,3H-吲哚基,吲哚基,吲唑基,嘌呤基,异喹啉基,喹啉基,酞嗪基,萘啶基,噌啉基,喹唑啉基,蝶啶基,4aH-咔唑基,咔唑基,β-咔啉基,菲啶基,吖啶基,嘧啶基,菲咯啉基,吩嗪基,噻唑基,异噻唑基,吩噻唑基(phenothiazolyl),异噁唑基,呋咱基和吩噁嗪基。典型的杂芳基包括噻吩基(例如噻吩-2-基和噻吩-3-基),呋喃基(例如2-呋喃基和3-呋喃基),吡咯基(例如吡咯-1-基,1H-吡咯-2-基和1H-吡咯-3-基),咪唑基(例如咪唑-1-基,1H-咪唑-2-基和1H-咪唑-4-基),四唑基(例如四唑-1-基和四唑-5-基),吡唑基(例如1H-吡唑-3-基,1H-吡唑-4-基和1H-吡唑-5-基),吡啶基(例如吡啶-2-基,吡啶-3-基和吡啶-4-基),嘧啶基(例如嘧啶-2-基,嘧啶-4-基,嘧啶-5-基和嘧啶-5-基),噻唑基(例如噻唑-2-基,噻唑-4-基和噻唑-5-基),异噻唑基(例如异噻唑-3-基,异噻唑-4-基和异噻唑-5-基),噁唑基(例如噁唑-2-基,噁唑-4-基和噁唑-5-基)和异噁唑基(例如异噁唑-3-基,异噁唑-4-基和异噁唑-5-基)。5-元杂芳基能够含有多至4个杂原子。6-元杂芳基能够含有多至3个杂原子。各杂原子独立地选自氮,氧和硫。
适宜的羧酸保护基团是熟知的和包括例如公开于Wuts,P.G.M.&Greene,T.W.,Greene's Protective Groups in Organic Synthesis,4rd Ed.,pp.16-430(J.Wiley&Sons,2007)的任何适宜的羧酸保护基团,通过援引将其全部并入本文。本领域技术人员熟悉保护基团的选择、附着和裂解并且理解许多不同的保护性基团是本领域已知的,使用一种保护性基团还是另一种取决于所计划的特定合成方案。适宜的羧酸保护基团包括例如甲基酯,叔丁基酯,苄基酯和烯丙基酯。
物质和方法
一般
全部试剂和溶剂商业购买(Aldrich,Acros,或Alfa Inc.)和不加进一步纯化使用,除非另有指定。溶剂通过分子筛系统干燥(Pure Solve Solvent PurificationSystem;Innovative Technology,Inc.)。1H和13C NMR谱图在Bruker Avance光谱仪上分别于400MHz和100MHz记录,并且指出NMR溶剂。化学位移按ppm(δ)、按Hz计的偶联常数J报告。多重度定义为单峰(s),二重峰(d),三重峰(t),宽峰(br),和多重峰(m)。高分辨率质谱(HRMS)数据用Agilent(Santa Clara,CA)G3250AA LC/MSD TOF系统获得。薄层色谱法(TLC)分析用Merck(Darmstadt,德国)硅胶60F254板进行。一般地,粗制化合物通过填充硅胶(Aldrich)的快速柱色谱法(FC)纯化。高效液相色谱(HPLC)在Agilent 1100系列系统上进行。γ计数器(Cobra II自动γ计数器,Perkin-Elmer)测量68Ga放射性。[68Ga]GaCl3的水溶液得自68Ge/68Ga发生器(iTG,德国)。固相萃取柱(SEP Light QMA,HLB 3cc)得自Waters(Milford,MA,USA)。[18F]NaF购自IBA(Somerset,NJ)。
方案1.合成化合物1a-h
实施例1a-h
配体的制备
1. 3,3'-(((2,2,13,13-四甲基-4,11-二氧代-3,12-二氧杂-6,9-二氮杂十四烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸二甲酯(4)
如方案1中概括,在100mL圆底烧瓶中将2,2'-(乙烷-1,2-二基二(氮烷二基))双乙酸二叔丁酯(2g,6.94mmol)和3-(4-羟基苯基)丙酸甲酯(2.63g,14.5mmol)溶于乙醇(50mL)和甲苯(50mL)。在搅拌下分批加入低聚甲醛(4.3g,145mmol),将悬浮液加热至回流过夜。然后除去溶剂。粗制产品用水洗涤,用二氯甲烷(DCM)萃取,干燥,过滤,蒸发,通过FC纯化,产生4,是无色油状物产品(3.94g,84.5%,(EtOAc/己烷=3/7)。1HNMR(400MHz,CDCl3)δ:7.00(dd,2H,J=2.0Hz,J=8.4Hz),6.77(d,2H,J=8.4Hz),6.74(d,2H,J=2.0Hz),3.70(s,4H),3.67(s,6H),3.17(s,4H),2.83(t,4H,J=7.8Hz),2.69(s,4H),2.57(t,4H,J=7.8Hz),1.46(s,18H)。HRMS计算值C36H53N2O10 672.3700;实测值,673.3680[M+H]+。
2. 3,3'-(((2,2,13,13-四甲基-4,11-二氧代-3,12-二氧杂-6,9-二氮杂十四烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸(5)
向搅拌的4(1g,1.48mmol)的甲醇(20mL)和H2O(20mL)溶液加入NaOH(5mmol,0.2g)。反应继续在室温下搅拌过夜,用1N HCl中和直至pH=7。然后减压除去绝大多数溶剂,用乙酸乙酯萃取,在MgSO4上干燥。粗制产品通过FC(二氯甲烷/甲醇/NH4OH,90/9/1,V/V/V)纯化,产生5,是白色沫状物(909mg,94.7%)。1H NMR(400MHz,CD3OD)δ:7.05(dd,J=2.4,2.0Hz,2H),6.93(d,J=2.0Hz,2H),6.72(d,J=8.4Hz,2H),3.80(s,4H),3.34-3.32(m,7H),2.85-2.80(m,8H),2.54-2.50(m,4H),1.489(s,18H)。13C NMR(100MHz,CD3OD)δ:176.42,170.14,132.02,130.05,128.91,121.21,115.39,81.80,55.34,54.67,49.78,36.49,30.11,26.98。HRMS计算值C34H48N2O10 644.3309;实测值,645.3483[M+H]+。
6a-h的一般合成程序
向搅拌的5(200mg,0.31mmol)和保护氨基酸或保护葡萄糖胺(0.31mmol)之一的二甲基甲酰胺(DMF)(20mL)溶液依次加入N,N-二异丙基乙胺(1mL),N-羟基苯并三唑水合物(HOBt)(84mg,0.62mmol),和1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)(118mg,0.62mmol)。混合物在室温下搅拌3小时,随后依次加入氨基亚甲基二膦酸四乙基酯(94mg,0.31mmol)和HBTU(118mg,0.62mmol)。混合物然后在室温下搅拌过夜,用EtOAc(50mL)稀释,用盐水洗涤(2×20mL),在Na2SO4上干燥,浓缩,通过FC(DCM/MeOH=10/1)纯化,产生希望产品。
6a:向搅拌的5(100mg,0.15mmol)和氨基亚甲基二膦酸四乙基酯(52mg,0.17mmol)的DMF(20mL)溶液依次加入三乙基胺(1mL),HOBt(20mg,0.15mmol)和EDCI(59mg,0.31mmol)。混合物用EtOAc(50mL)稀释,用盐水洗涤(2×25mL),在Na2SO4上干燥,浓缩,通过FC纯化(DCM/MeOH/NH4OH=90/9/1),产生6a,是白色沫状物(63mg,44.3%)。1HNMR(400MHz,CDCl3)δ:7.11-7.06(m,1H),7.03-7.00(m,1H),6.80-6.72(m,4H),4.26-4.20(m,8H),3.52-3.50(m,4H),3.34(s,1H),2.91-2.78(m,6H),2.68-2.66(m,4H),2.63-2.56(m,6H),1.46(s,18H),1.36(t,J=6.4Hz,12H)。HRMS计算值C43H69N3O15P2 929.4204;实测值930.4209[M+H]+。
6b:按照一般程序,将5(200mg,0.31mmol)用1,3,4,6-四-O-乙酰基-2-氨基-2-脱氧-吡喃葡萄糖盐酸盐(118mg,0.31mmol)处理,提供6b(111mg,28.4%),是无色油状物。1HNMR(400MHz,CDCl3)δ:9.50(s,1H),7.01-6.97(m,2H),6.79-6.66(m,5H),5.34-5.24(m,1H),5.14-4.98(m,1H),4.14-4.09(m,8H),3.69-3.59(m,6H),3.20-3.18(m,4H),2.87-2.47(m,8H),2.67-2.53(m,6H),2.41-2.37(m,2H),1.45(s,18H),1.35-1.30(m,12H),1.27-1.23(m,12H)。13C NMR(100MHz,CDCl3)δ:172.66,171.09,170.89,170.68,170.20,169.46,169.24,155.72,155.61,131.20,130.99,129.15,129.04,128.79,121.60,116.27,92.46,82.14,82.09,72.67,2.43,68.11,63.81,63.46,61.74,60.34,57.58,56.08,55.87,55.43,52.77,50.02,38.42,37.82,30.69,30.06,28.03,20.81,20.68,20.54,16.32,16.28,14.16。HRMS计算值C57H88N4O23P2 1258.5315,实测值:1259.5321[M+H]+。
6c:按照一般程序,将5(200mg,0.31mmol)用氨基乙酸叔丁酯盐酸盐(52mg,0.31mmol)处理,提供6c(100mg,31.1%),是无色油状物。1H NMR(400MHz,CDCl3)δ:9.53(s,2H),7.05-7.00(m,2H),6.77-6.74(m,4H),4.24-4.10(m,8H),3.70-3.67(m,3H),3.19-3.16(m,6H),2.95-2.88(m,6H),2.69-2.64(m,4H),2.57-2.47(m,4H),1.46(s,27H),1.35-1.20(m,12H)。13C NMR(100MHz,CDCl3)δ:172.35,170.05,155.82,155.71,131.38,130.97,129.15,128.88,121.56,117.04,116.39,82.09,63.66,57.81,55.70,50.22,42.01,40.58,38.40,38.02,30.48,28.05,16.33。HRMS计算值C49H80N4O16P2 1042.5045,实测值:1043.6564[M+H]+。
6d:按照一般程序,将5(200mg,0.31mmol)用L-丙氨酸叔丁基酯盐酸盐(56mg,0.31mmol)处理,提供6d(103mg,31.7%),是无色油状物。1H NMR(400MHz,CDCl3)δ:7.03-6.97(m,2H),6.84-6.76(m4H),4.21-4.09(m,8H),3.70(s,4H),3.46(s,1H),3.21(s,4H),2.87-2.81(m,6H),2.72-2.61(m,4H),2.49-2.46(m,4H),1.46(s,27H),1.31-1.23(m,15H)。13C NMR(100MHz,CDCl3)δ:172.39,171.85,170.17,155.57,131.41,131.07,129.40,128.98,121.50,116.31,115.44,82.14,64.03,63.82,63.57,57,78,55.65,50.29,48.59,38.55,37.77,30.48,28.03,27.95。HRMS计算值C50H82N4O16P2 1056.5201,实测值:1057.7004[M+H]+。
6e:按照一般程序,将5(200mg,0.31mmol)用L-天冬氨酸二叔丁基酯盐酸盐(87mg,0.31mmol)处理,提供6e(110mg,30.8%),是无色油状物。1H NMR(400MHz,CDCl3)δ:7.03-6.98(m,2H),6.80-6.73(m,4H),5.11-4.98(m,1H),4.20-4.08(m,8H),3.71-3.66(m,6H),3.46(s,1H),3.16(s,4H),2.96-2.83(m,6H),2.70-2.65(m,6H),2.58-2.55(m,1H),2.48-2.43(m,1H),1.46(s,36H),1.35-1.25(m,12H)。13C NMR(100MHz,CDCl3)δ:172.01,170.43,170.19,170.14,169.93,155.71,155.63,131.30,131.00,129.34,129.26,128.92,128.84,121.62,121.54,116.34,82.29,82.07,81.55,64.04,63.79,57.90,55.64,50.37,49.02,43.23,42.60,38.49,37.78,37.50,30.87,30.64,30.45,28.03,16.30,16.26,16.22。HRMS计算值C55H90N4O18P2 1156.5725,实测值:1157.7476[M+H]+。
6f:按照一般程序,将5(200mg,0.31mmol)用L-谷氨酸二叔丁基酯盐酸盐(91mg,0.31mmol)处理,提供6f(118mg,32.8%),是无色油状物。1H NMR(400MHz,CDCl3)δ:7.03-6.99(m,2H),6.76-6.74(m,4H),5.13-4.99(m,1H),4.22-4.10(m,8H),3.69(s,4H),3.47(s,1H),3.18(s,4H),2.87-2.85(m,4H),2.69(s,4H),2.49-2.44(s,4H),2.29-2.13(m,2H),2.11-2.05(m,1H),1.92-1.82(m,1H),1.46(s,36H),1.35-1.26(m,12H)。13C NMR(100MHz,CDCl3)δ:172.25,172.08,171.41,171.24,170.00,155.94,155.74,131.33,130.92,129.11,128.88,121.56,116.39,82.21,82.06,82.04,63.67,57.97,55.56,52.16,50.32,43.33,38.55,38.00,3.52,30.65,30.46,28.07,28.05,27.98,27.71,16.35,16.32,16.28。HRMS计算值C56H92N4O18P2 1170.5882,实测值:1171.5891[M+H]+。
1a-f的一般合成程序
向搅拌的6a-f的乙腈(1mL)溶液加入溴三甲基硅烷,混合物继续在室温下搅拌过夜。然后减压除去溶剂,加入三氟乙酸(TFA)(2mL),反应再次在室温下搅拌过夜。然后减压除去混合物,残余物从乙醚/EtOH重结晶,产生1a-f,是白色固体。
1a:按照一般程序,将6a(50mg,0.054mmol)用溴三甲基硅烷(73mg,0.47mmol)处理,提供1a(31mg,82.3%),是白色固体。1HNMR(400MHz,二甲亚砜,DMSO-d6)δ:7.90-7.86(m,4H),7.36-7.33(m,2H),3.77-3.75(m,5H),3.33-3.29(m,6H),2.66-2.61(m,4H)。
1b:将甲醇钠(25mg,0.47mmol)与溶于甲醇(5mL)的6b(60mg,0.047mmol)在室温下混合和搅拌2小时。脱保护通过LC-MS监测,反应用1N HCl中和至pH=7。然后减压除去绝大多数溶剂,用乙酸乙酯萃取。粗制产品在MgSO4上干燥,不加进一步纯化并溶于乙腈(1.0mL),随后加入溴三甲基硅烷(1.0mL)。然后在室温下搅拌混合物过夜,随后减压除去溶剂,加入醚,过滤,收集固体。然后将固体溶于TFA(2mL),在室温下搅拌反应过夜。减压除去上述混合物,残余物从醚/EtOH重结晶,提供1b,是浅黄色固体。1HNMR(400MHz,DMSO-d6)δ:7.91(s,1H),7.34-7.06(m,5H),6.80-6.77(m,2H),4.02-3.89(m,10H),3.62-3.56(m,5H),3.23-3.16(m,5H),2.72-2.70(m,4H),2.45-2.34(m,2H),2.05-1.98(m,2H)。13C NMR(100MHz,DMSO-d6)δ:173.17,171.41,171.11,170.72,158.72,158.40,155.08,154.77,132.38,131.91,131.43,130.28,119.49,118.97,115.89,115.72,65.36,55.34,52.80,51.69,50.13,35.64,30.64,21.60,21.11,15.61。
1c:按照一般程序,将6c(50mg,0.047mmol)用溴三甲基硅烷(73mg,0.47mmol)处理,提供1c(29mg,80.1%),是白色固体。1HNMR(400MHz,DMSO-d6)δ:7.11-7.09(m,4H),6.73-6.70(m,2H),3.71(s,4H),3.46(s,1H),2.98-2.68(m,8H),2.51-2.41(m,10H)。13CNMR(100MHz,DMSO-d6)174.95,173.86,172.99,161.24,154.93,132.73,118.37,116.20,115.11,4.18,49.61,40.91,30.03,21.32。
1d:按照一般程序,将6d(50mg,0.047mmol)用溴三甲基硅烷(73mg,0.47mmol)处理,提供1d(30mg,81.5%),是白色固体。1HNMR(400MHz,DMSO-d6)δ:7.09-7.05(m,4H),6.78-6.75(m,2H),3.70(s,4H),3.42(s,1H),2.73-2.68(m,6H),2.54-2.45(m,10H),1.36-1.32(m,3H)。13CNMR(100MHz,DMSO-d6)δ:174.71,172.28,171.96,170.82,159.13,155.07,132.38,132.26,130.40,118.66,15.89,115.79,65.36,56.62,47.88,22.87,18.93。
1e:按照一般程序,将6e(50mg,0.043mmol)用溴三甲基硅烷(65mg,0.43mmol)处理,提供1e(30mg,81.3%),是白色固体。1HNMR(400MHz,DMSO-d6)δ:8.18(s,1H),7.13-7.01(m,4H),6.81-6.78(m,2H),3.36-3.31(s,2H),3.20(s,6H),2.73-2.66(m,6H),2.56-2.54(m,2H),2.45(s,4H),2.37-2.34(m,4H)。13C NMR(100MHz,DMSO-d6)δ:172.96,172.13,171.94,170.59,158.86,158.50,158.14,155.02,154.89,65.36,56.49,49.03,37.44,36.55,30.58,19.00,15.61。
1f:按照一般程序,将6f(50mg,0.042mmol)用溴三甲基硅烷(65mg,0.42mmol)处理,提供1f(29mg,80.9%),是白色固体。1HNMR(400MHz,DMSO-d6)δ:7.11-7.08(m,4H),6.72-6.69(m,2H),3.72(s,4H),3.45(s,1H),3.31(s,1H),2.72-2.68(m,6H),2.51-2.45(m,6H),2.39-2.34(m,4H)。13CNMR(100MHz,DMSO-d6)δ:174.71,172.28,171.96,170.82,159.13,158.81,158.49,154.95,154.79,132.38,132.26,130.40,118.66,115.89,115.79,65.36,56.52,47.88,22.87,18.93,17.61。
合成1g
向搅拌的5(50mg,0.054mmol)和(S)-二-叔丁基2-(3-((S)-6-(6-氨基己酰胺基)-1-叔丁氧基-1-氧代己烷-2-基)脲基)戊烷二酸酯(20mg,0.11mmol)的20mL DMF溶液依次加入1ml N,N-二异丙基乙胺,HOBt(15mg,0.11mmol)和EDCI(118mg,0.62mmol)。混合物在室温下搅拌过夜。混合物用EtOAc(50mL)稀释,用盐水洗涤(2×20mL),在Na2SO4上干燥,浓缩,通过FC(DCM/MeOH=10/1)纯化,产生粗制产品6g(46mg,61.2%)。向搅拌的6g(30mg,0.021mmol)的1mL乙腈溶液加入溴三甲基硅烷(16mg,0.1mmol)。混合物在室温下搅拌过夜,减压除去溶剂,加入TFA(4mL),在室温下搅拌反应过夜。然后减压除去上述混合物,残余物从醚/EtOH重结晶,产生1g,是白色固体产品(21mg,86.4%)。1HNMR(400MHz,DMSO-d6)δ:7.85-7.69(m,2H),7.18-7.08(m,4H),6.89-6.67(m,2H),6.89-6.67(m,1H),6.34(s,1H),3.49-3.21(m,10H),2.89-2.65(m,10H),2.49-2.18(m,7H),2.19-1.88(m,6H),1.77-1.55(m,4H),1.48-1.09(m,8H)。13CNMR(100MHz,DMSO-d6)13C NMR(100MHz,CDCl3)δ:177.48,174.95,174.58,174.17,172.49,171.85,171.50,170.40,170.12,159.31,158.95,158.58,157.79,154.99,132.55,132.39,130.63,120.39,118.51,117.50,115.91,114.61,111.71,65.35,60.21,56.50,52.75,52.15,35.82,30.36,29.28,27.99,25.49,23.08,18.97,15.59。
合成1h
向搅拌的化合物6a(0.4g,0.43mmol)和化合物2-氨基乙基-一-酰胺-DOTA-三(叔-Bu酯)(0.29g,0.43mmol)的20mL DMF溶液依次加入2mL DIEPA,HOBt(6mg,0.043mmol)和EDCI(0.16g,0.86mmol)。在室温下搅拌反应过夜。混合物用100mLEtOAc稀释,用盐水洗涤(25×2mL),在Na2SO4上干燥,浓缩和通过combiflash(DCM/MeOH/NH4OH=90/9/1)纯化,提供6h,是白色沫状物(0.39g,60%)。1HNMR(400MHz,CDCl3)δ:8.04(s,1H),7.90(s,1H),6.80-6.82(m,2H),6.65(s,1H),6.62(s,1H),6.53(t,J=8.2Hz,2H),4.96-4.84(m,1H),4.00-3.92(m,8H),3.50(s,4H),3.23-3.15(m,16H),3.03(s,6H),2.68-2.62(m,8H),2.49(s,6H),2.41-2.31(m,8H),1.28(s,45H),1.16-1.09(m,3H)。13C NMR(100MHz,CDCl3)δ:173.64,172.33,172.04,171.67,170.06,155.44,155.13,131.83,131.00,129.25,129.10,128.83,128.67,121.26,116.03,115.84,81.80,81.77,81.73,81.67,77.33,77.01,63.56,63.54,57.68,57.55,55.89,55.52,55.45,55.29,53.96,52.58,49.94,43.25,42.25,39.14,38.99,38.10,37.51,30.87,30.32,27.83,27.78,27.72,16.16,16.13,16.10,16.07。HRMS计算值C73H125N9O21P2 1525.8465;实测值,1526.8258[M+H]+。向搅拌的6h(0.4g,0.26mmol)的10mL乙腈溶液加入1.5mL溴三甲基硅烷。混合物继续在室温下搅拌过夜。然后减压除去溶剂,加入TFA(4ml),反应再次在室温下搅拌过夜。然后减压除去混合物,残余物通过EZcombflash纯化,提供1h(0.27g,93.1%)。1HNMR(400MHz,CDCl3)δ:13C NMR(100MHz,CDCl3)δ172.44,172.10,169.95,159.37,159.01,158.63,155.14,132.84,132.45,130.98,120.08,117.19,116.01,114.31,111.44,69.35,65.36,60.21,56.48,55.20,54.34,53.00,51.68,51.05,49.63,48.93,48.43,30.60,22.90,21.21,20.92,18.99,15.61,14.54,13.92HRMS计算值C45H69N9O21P21133.4083;实测值,1134.4131[M+H]+。
方案2
制备[natGa3+]1a
实施例2
合成化合物[natGa3+]1a
如方案2中所示,将0.1mL H2O中的GaCl3(1.7mg,0.01mmol)加至1a(7mg,0.01mmol)的DMSO(0.5mL)溶液。将反应溶液调节至pH 4,在室温下搅拌过夜。然后减压蒸发溶液,粗制产品从乙醇和H2O重结晶,产生[natGa3+]1a,是白色固体(6.8mg,90.2%)。1HNMR(400MHz,DMSO-d6)δ:7.38(s,1H),7.25-7.20(m,4H),6.88(s,1H),3.61-3.52(m,4H),3.49(s,2H),3.33-3.15(m,6H),2.71(s,4H),2.55(s,2H),2.45(s,2H)。13C NMR(400MHz,DMSO-d6)δ:174.39,173.04,171.69,168.39,168.23,155.46,155.36,133.53,132.49,132.12,131.80,117.00,116.19,115.51,70.19,53.10,49.04,37.26,35.90,29.83,22.64。
方案3
合成2,2'-(乙烷-1,2-二基二((5-(3-((二膦酰基甲基)氨基)-3-氧代丙基)-2-羟基苄基)氮烷二基))二乙酸(2)
实施例3
合成化合物2
1.((3-(3-(((2-((5-(3-((二(二乙氧基磷酰基)甲基)氨基)-3-氧代丙基)-2-羟基苄基)(2-(叔丁氧基)-2-氧代乙基)氨基)乙基)(2-(叔丁氧基)-2-氧代乙基)氨基)甲基)-4-羟基苯基)丙酰胺基)亚甲基)二膦酸(7)
如方案3中的概括,将三乙基胺(2mL)、HOBt(44mg,0.33mmol)和HBTU(129mg,0.34mmol)依次加入搅拌的5(100mg,0.15mmol)和氨基亚甲基二膦酸四乙基酯(52mg,0.33mmol)的20mL DMF溶液。混合物在室温下搅拌过夜,用EtOAc(50mL)稀释,用盐水(20×2mL)洗涤,在Na2SO4上干燥,浓缩,通过FC(DCM/MeOH/NH4OH=90/9/1)纯化,产生7,是白色沫状物(116mg,41.2%)。1HNMR(400MHz,CDCl3)δ:7.01(t,J=3.6Hz,12H),6.78-6.75(m,4H),4.22-4.14(m,16H),3.71(s,4H),3.18(s,4H),2.89-2.85(m,6H),2.70(s,4H),2.56-2.52(t,J=3.6Hz,4H),1.46(s,18H),1.36-1.30(m,24H)。HRMS计算值C52H90N4O20P4 1214.5099;实测值1215.5061[M+H]+。
2. 2,2'-(乙烷-1,2-二基二((5-(3-((二膦酰基甲基)氨基)-3-氧代丙基)-2-羟基苄基)氮烷二基))二乙酸(2)
向搅拌的7(60mg,0.049mmol)的乙腈(1mL)溶液加入溴三甲基硅烷(75mg,0.49mmol)。混合物在室温下搅拌过夜,减压除去溶剂,加入TFA(2mL),随后反应再次在室温下搅拌过夜。然后减压除去混合物,残余物从醚/EtOH重结晶,产生2,是白色固体(34mg,82.1%)。1HNMR(400MHz,DMSO-d6)δ:7.24-7.20(m,4H),6.88(d,J=4.32Hz,2H),4.41-4.37(m,4H),3.87(s,2H),2.88-2.81(m,6H),2.61-2.68(m,4H),2.35-2.33(m,4H)。
方案4
2,2'-(((((丙烷-1,3-二基二(氮烷二基))二(3-氧代丙烷-3,1-二基))二(2-羟基-5,1-亚苯基))二(亚甲基))二((2-((羧甲基)(5-(3-((二膦酰基甲基)氨基)-3-氧代丙基)-2-羟基苄基)氨基)乙基)氮烷二基))二乙酸(3)
实施例4
合成化合物3
1. 2,2'-(((((丙烷-1,3-二基二(氮烷二基))二(3-氧代丙烷-3,1-二基))二(2-羟基-5,1-亚苯基))二(亚甲基))二((2-((5-(3-((二(二乙氧基磷酰基)甲基)氨基)-3-氧代丙基)-2-羟基苄基)(2-(叔丁氧基)-2-氧代乙基)氨基)乙基)氮烷二基))双乙酸二叔丁基酯(8)
向搅拌的1a(50mg,0.054mmol)和1,3-二氨基丙烷(2mg,0.027mmol)的10mL DMF溶液依次加入三乙基胺(2mL)、HOBt(14mg,0.11mmol)和EDCI(40mg,0.22mmol),如方案4中所示。混合物在室温下搅拌过夜,用EtOAc(50mL)稀释,用盐水(2×20mL)洗涤,在Na2SO4上干燥,浓缩,通过FC(DCM/MeOH/NH4OH=90/9/1)纯化,产生8,是白色沫状物(27mg,53.2%)。HRMS计算值C90H146N8O28P4[M]+2H+949.9577;实测值949.9581[M]+2H+。
2. 2,2'-(((((丙烷-1,3-二基二(氮烷二基))二(3-氧代丙烷-3,1-二基))二(2-羟基-5,1-亚苯基))二(亚甲基))二((2-((羧甲基)(5-(3-((二膦酰基甲基)氨基)-3-氧代丙基)-2-羟基苄基)氨基)乙基)氮烷二基))二乙酸(3)
向搅拌的8(20mg,0.01mmol)的乙腈(1mL)溶液,加入溴三甲基硅烷(16mg,0.1mmol),混合物在室温下搅拌过夜。减压除去溶剂,加入TFA(2mL),反应再次在室温下搅拌过夜。然后减压除去混合物,残余物从醚/EtOH重结晶,产生3,是白色固体产品(12mg,81.5%)。1HNMR(400MHz,DMSO-d6)δ:7.11-7.07(m,8H),6.74-6.68(m,4H),3.73(s,8H),3.43(s,2H),3.08-2.92(m,8H),2.82-2.72(m,12H),2.67-2.56(m,10H),2.49-2.31(m,8H)。
实施例5
用68Ga放射性标记
0.05N HCl溶液中洗脱的镓-68得自68Ge/68Ga发生器(iTG,德国)。68Ga标记BPAMD的制备用预先报告的标记程序实现。
方案5:化合物1a-h的68Ga标记
方案6:化合物2的68Ga标记
方案7:化合物3的68Ga标记
为了制备新的HBED-CC二膦酸盐/酯衍生物用于68Ga标记,制备配体1a-h(200μM,在0.1N NaOAc中)、2(200μM,在0.1N NaOAc中)和3(200μM,在0.1N NaOAc中)的储备溶液并用于各研究。68Ga标记进行如下:将68Ga溶液加入不同的配体1a-h、2和3的溶液,如方案5-7所示。1a-h、2和3的标记条件是,将0.05N HCl中的200μL 68GaCl3和在0.1N NaOAc中的200μM的1a-h、2或3(250μL)配体溶液在室温下保持10分钟(最终浓度:111μM,pH 5.0)。在将反应混合物保持在室温下5-10分钟之后确定放射性标记收率。[68Ga]1a-h、[68Ga]2和[68Ga]3的放射化学收率通过Macherey Nagel纤维素TLC板(Polygram Cel 300)确定,用由2份0.1NNaOAc(10mL,pH 4.10,88mL丙酮)和1份2,4-戊二酮组成的溶剂混合物展开。在各TLC板上的活性分布借助放射自显影术用Typhoon FLA 7000激光扫描仪测量。HPLC分析用C18柱进行(Supelco Ascentis C18 150×4.6mm 5μ,MeOH:0.1%TFA/H2O(梯度:0分钟,100%0.1%TFA/H2O;6分钟,0%0.1%TFA/H2O,流速,2mL/min)。
为了体内成像研究,需要较大量的68Ga标记试剂。在含水NaOAc缓冲剂(200μL,2.0M)中进行标记:将配体溶液(200μL,200μM,在0.1N NaOAc中)加入68Ga溶液(400μL,在0.6N HCl中)/H2O(200μL)。溶液的最终pH是4.10。
实施例6
在小鼠中的体内生物分布
生物分布实验进行如下:将68Ga标记的1a-h,2,3,BPAMD和[18F]NaF经静脉内给予普通健康雄性CD-1小鼠(25-30g)。注射活性是20-30μCi/动物。于2,30,60和120分钟注射后处死动物。收获、称量有关器官,通过γ计数器测量放射性计数。各样品的生物分布计算为注射剂量/克润湿组织重量的百分比(%ID/g)。收获胫骨和股骨并作为骨样品计数。
实施例7
体外结合至羟基磷灰石
将羟基磷灰石(20mg,Sigma-Aldrich,试剂级粉末)在等渗盐水(1mL)中温育24小时。随后,将68Ga标记的1a-h,2,3,BPAMD或[18F]NaF(1μCi)加至羟基磷灰石悬浮液。涡流搅拌10秒之后,将悬浮液在室温下温育10分钟。然后于10,000rpm离心样品3分钟,除去上清液。羟基磷灰石级分用盐水(1mL)洗涤两次。用γ计数器测量经合并上清液和羟基磷灰石级分中的放射性。68Ga配合物结合至羟基磷灰石的比例测定为羟基磷灰石吸收的68Ga百分比。
实施例8
小鼠中的微-PET成像研究
[68Ga]1a,[68Ga]BPAMD和[18F]NaF在普通CD-1雄性小鼠中测试。[68Ga]1g在携带PSMA表达性LNCaP肿瘤的裸鼠中测试。小鼠通过尾部静脉注射接受300-500uCi放射性示踪剂。PET成像在异氟烷麻醉(2%异氟烷,1.5L/min氧)下进行。微PET成像用小动物PET(Mosaic by Phillips,USA)进行。在PET测量期间,将动物置于俯卧位。注射放射性示踪剂60分钟后,数据采集进行15分钟。
结果
合成
靶标化合物1a-h,2和3的合成通过描述于方案1、3和4的反应准备。为了制备保护的化合物5,通过2,2'-(乙烷-1,2-二基二(氮烷二基))双乙酸二叔丁基酯和3-(4-羟基苯基)丙酸甲酯的曼尼希反应以优异收率(84.5%)合成化合物4。4的羧酸官能团用OtBu或OMe酯基团分开地保护,化合物4的甲基酯通过NaOH水解选择性地除去,提供化合物5(94.7%收率)。为了制备二膦酸酯衍生物,化合物5用EDCI和HOBt在DMF中活化。加入氨基亚甲基二膦酸四乙基酯,提供希望的保护二膦酸酯6a,44.3%收率。在室温下用三甲基溴硅烷处理6a过夜之后,除去溶剂,在TFA中再搅拌一夜,同时除去膦酸酯乙基酯基团和叔丁基酯,提供1a(82.3%收率)。
为了产生携带不同基团的6c,首先将氨基酸基团加入保护的HBED-CC 5核心以产生中间体,原因是氨基亚甲基二膦酸四乙基酯具有与保护的氨基酸相比更高的立体位阻。用氨基亚甲基二膦酸四乙基酯进行又一中间反应,产生6c。在通过与1a相似的方法用三甲基溴硅烷和TFA处理6c之后,获得6c,80.1%收率。该途径是简单和通用的。用相似反应程序和不同衍生物制备1b-h。成功实现希望二膦酸盐/酯的合成并且容易控制。
用68GaCl3放射性标记1a-h、2和3
放射性[68Ga]1a-h、[68Ga]2和[68Ga]3的制备实现如下:将0.05M HCl中的68GaCl3与在0.1N NaOAc溶液中的适宜量前体1a-h、2或3混合,反应保持在室温下10分钟。放射化学纯度通过TLC和HPLC方法测量。TLC结果显示,68Ga配合物展示Rf=0-0.1而游离68Ga3+产品显示Rf=0.8-0.9。如期望的,HPLC分析揭示Ga-HBED-CC-BP配合物的多个峰。[68Ga]1a-h、[68Ga]2和[68Ga]3显示4-5.5分钟的保留时间,而游离68GaCl3显示1分钟的保留时间。
[natGa]1a配体合成如下:将1a与GaCl3在DMSO中在室温下反应过夜。然后光谱表征化合物。
重要地,[68Ga]1a-h和[68Ga]2的制备能够在室温下于5至10分钟内以111μM的配体浓度容易地实现,而已知试剂[68Ga]BPAMD的制备则需要在80-90℃加热5-10分钟。新的骨成像剂[68Ga]1a-h和[68Ga]2可以提供试剂盒配制剂,其能够方便地用于核医疗诊所,而不需要加热、冷却和附近的回旋加速器来制备[18F]NaF。
合适的金属离子比如氯化Lu(III)能够鉴定用于化合物1h的DOTA部分的选择性放射性标记,其基于金属配合能力和金属DOTA和HBED配合物的稳定性常数的差异。选择性放射性标记的条件能够在与上述68Ga(III)相似的反应条件下常规地优化的,例外是接受可以需要加热177Lu(III)和配体1h的反应混合物。
在普通小鼠中的体内生物分布
为了评价骨摄取,将68Ga标记的配合物和已知骨成像剂[18F]NaF经静脉内注入普通小鼠。生物分布研究结果如表4所示显示的是,[18F]NaF、[68Ga]1a和[68Ga]2于iv注射后60分钟在普通小鼠中的骨摄取分别是24.6±3.2、23.5±1.4和19.7±4.2(%剂量/g)。骨/肌肉指出在普通小鼠中[18F]NaF、[68Ga]1a和[68Ga]2于iv注射60分钟后的信号/背景比分别是291、94.5和82.7。展示的是,[68Ga]BPAMD与新试剂[68Ga]1a-h和[68Ga]2相比显示更低的骨摄取和保留。尤其是,[68Ga]1a、[68Ga]1g、[68Ga]1h和[68Ga]2展示与对[18F]NaF所观察到的相比优异的骨摄取和快速肾分泌。结果表明[68Ga]1a、[68Ga]1g、[68Ga]1h和[68Ga]2可能在成像人类骨摄取和可能骨转移方面是可比拟的,类似目前的特选试剂[18F]NaF。
表4a-g:骨成像剂:[18F]NaF、[68Ga]BPAMD、[68Ga]1a-h、[177Lu]1h、[68Ga]2、[68Ga]3和[68Ga]HBED-CC在普通CD-1雄性小鼠中的生物分布(%剂量/g,Avg±SD,n=3)
a.放射性示踪剂:[18F]NaF
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 5.56±0.37 | 0.64±0.08 | 0.15±0.01 | 0.03±0.00 |
心脏 | 2.80±0.24 | 0.96±0.23 | 0.18±0.02 | 0.04±0.00 |
肌肉 | 1.50±0.06 | 0.33±0.11 | 0.09±0.02 | 0.04±0.04 |
肺 | 3.37±0.17 | 0.55±0.11 | 0.14±0.01 | 0.04±0.01 |
肾 | 10.4±1.22 | 1.70±0.62 | 0.68±0.36 | 0.57±0.43 |
脾 | 2.33±0.14 | 0.93±0.56 | 0.12±0.02 | 0.03±0.01 |
胰 | 1.76±0.07 | 0.42±0.27 | 0.07±0.00 | 0.02±0.00 |
肝 | 2.56±0.24 | 0.65±0.17 | 0.13±0.01 | 0.03±0.01 |
皮肤 | 2.35±0.45 | 0.51±0.11 | 0.11±0.02 | 0.03±0.00 |
脑 | 0.22±0.07 | 0.10±0.02 | 0.06±0.01 | 0.04±0.00 |
骨 | 10.8±0.51 | 24.2±2.71 | 24.6±3.18 | 25.2±3.89 |
b.放射性示踪剂:[68Ga]BPAMD
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 9.45±0.55 | 1.02±0.19 | 0.93±0.06 | 0.90±0.41 |
心脏 | 2.74±0.23 | 0.29±0.02 | 0.37±0.06 | 0.26±0.07 |
肌肉 | 1.63±0.35 | 0.55±0.11 | 0.31±0.04 | 0.29±0.06 |
肺 | 4.58±0.36 | 0.50±0.16 | 0.51±0.09 | 0.45±0.10 |
肾 | 22.1±8.80 | 1.46±0.19 | 2.88±1.51 | 1.09±0.26 |
脾 | 1.90±0.14 | 0.22±0.14 | 0.21±0.02 | 0.25±0.08 |
胰 | 1.73±0.11 | 0.27±0.14 | 0.30±0.02 | 0.33±0.07 |
肝 | 1.92±0.31 | 0.22±0.02 | 0.25±0.03 | 0.31±0.11 |
皮肤 | 2.57±0.53 | 0.39±0.15 | 0.60±0.08 | 0.55±0.04 |
脑 | 0.26±0.01 | 0.06±0.02 | 0.04±0.00 | 0.03±0.01 |
骨 | 7.07±0.94 | 10.5±0.6 | 9.21±0.90 | 9.62±0.71 |
c.放射性示踪剂:[68Ga]1a
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 9.39±0.93 | 0.45±0.10 | 0.20±0.06 | 0.07±0.03 |
心脏 | 3.28±0.13 | 0.22±0.02 | 0.12±0.02 | 0.07±0.01 |
肌肉 | 1.80±0.16 | 0.17±0.03 | 0.08±0.02 | 0.05±0.01 |
肺 | 4.28±0.21 | 0.38±0.03 | 0.21±0.03 | 0.12±0.03 |
肾 | 31.2±1.92 | 1.54±0.29 | 1.63±0.71 | 0.92±0.10 |
脾 | 1.89±0.20 | 0.17±0.01 | 0.10±0.02 | 0.09±0.03 |
胰 | 1.58±0.10 | 0.30±0.27 | 0.09±0.02 | 0.05±0.01 |
肝 | 1.95±0.15 | 0.32±0.20 | 0.17±0.01 | 0.14±0.02 |
皮肤 | 2.18±0.28 | 0.42±0.12 | 0.19±0.05 | 0.13±0.03 |
脑 | 0.31±0.10 | 0.02±0.01 | 0.02±0.01 | 0.01±0.00 |
骨 | 8.60±0.85 | 16.0±1.22 | 23.5±1.42 | 23.9±1.99 |
d.放射性示踪剂:[68Ga]1b
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 9.22±0.83 | 0.83±0.04 | 0.39±0.06 | 0.21±0.06 |
心脏 | 3.01±0.23 | 0.62±0.04 | 0.37±0.02 | 0.28±0.04 |
肌肉 | 1.79±0.28 | 0.24±0.03 | 0.13±0.01 | 0.09±0.01 |
肺 | 5.11±0.28 | 1.31±0.29 | 0.96±0.05 | 0.86±0.03 |
肾 | 18.5±2.45 | 3.21±1.59 | 2.65±0.44 | 2.71±0.17 |
脾 | 2.03±0.13 | 0.75±0.22 | 0.66±0.15 | 0.53±0.04 |
胰 | 1.51±0.06 | 0.24±0.02 | 0.11±0.01 | 0.08±0.01 |
肝 | 2.58±0.22 | 1.20±0.10 | 1.15±0.13 | 1.22±0.07 |
皮肤 | 2.55±0.58 | 0.60±0.02 | 0.26±0.04 | 0.18±0.01 |
脑 | 0.20±0.04 | 0.03±0.01 | 0.02±0.01 | 0.02±0.01 |
骨 | 8.34±0.88 | 16.6±1.37 | 19.4±2.05 | 17.1±3.70 |
e.放射性示踪剂:[68Ga]1c
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 11.7±0.55 | 1.34±0.32 | 0.64±0.17 | 0.41±0.07 |
心脏 | 4.57±0.45 | 0.49±0.07 | 0.24±0.08 | 0.19±0.03 |
肌肉 | 1.68±0.11 | 0.23±0.05 | 0.14±0.01 | 0.16±0.01 |
肺 | 5.66±0.24 | 0.84±0.11 | 0.42±0.08 | 0.31±0.06 |
肾 | 27.7±5.46 | 2.58±0.05 | 1.88±0.10 | 2.05±0.27 |
脾 | 3.41±0.08 | 0.97±0.01 | 0.74±0.10 | 0.71±0.29 |
胰 | 1.99±0.23 | 0.39±0.05 | 0.23±0.02 | 0.20±0.03 |
肝 | 4.78±0.18 | 2.21±0.27 | 1.85±0.11 | 1.99±0.09 |
皮肤 | 2.05±0.16 | 0.53±0.18 | 0.33±0.03 | 0.31±0.04 |
脑 | 0.27±0.06 | 0.05±0.02 | 0.03±0.01 | 0.02±0.01 |
骨 | 8.40±1.32 | 11.3±0.26 | 14.7±0.66 | 16.1±2.71 |
f.放射性示踪剂:[68Ga]1d
g.放射性示踪剂:[68Ga]1e
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 8.31±0.57 | 0.57±0.12 | 0.11±0.02 | 0.08±0.02 |
心脏 | 2.55±0.06 | 0.26±0.04 | 0.08±0.00 | 0.06±0.01 |
肌肉 | 1.71±0.19 | 0.25±0.03 | 0.06±0.00 | 0.04±0.01 |
肺 | 4.00±0.20 | 0.42±0.08 | 0.15±0.01 | 0.12±0.02 |
肾 | 24.8±3.02 | 2.26±0.27 | 2.12±0.55 | 1.41±0.28 |
脾 | 1.72±0.19 | 0.19±0.02 | 0.09±0.01 | 0.06±0.01 |
胰 | 1.27±0.07 | 0.17±0.05 | 0.06±0.01 | 0.04±0.01 |
肝 | 1.90±0.13 | 0.27±0.02 | 0.14±0.01 | 0.14±0.02 |
皮肤 | 2.54±0.26 | 0.86±0.22 | 0.12±0.01 | 0.12±0.03 |
脑 | 0.20±0.04 | 0.02±0.01 | 0.01±0.00 | 0.01±0.01 |
骨 | 8.82±0.77 | 16.5±0.56 | 14.9±1.45 | 17.6±2.61 |
h.放射性示踪剂:[68Ga]1f
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 8.98±0.68 | 0.52±0.05 | 0.18±0.04 | 0.09±0.01 |
心脏 | 3.53±0.57 | 0.23±0.01 | 0.11±0.01 | 0.07±0.01 |
肌肉 | 2.10±0.12 | 0.23±0.01 | 0.06±0.00 | 0.04±0.01 |
肺 | 5.01±0.81 | 0.42±0.03 | 0.21±0.01 | 0.13±0.01 |
肾 | 24.7±3.13 | 2.05±0.52 | 1.59±0.72 | 1.08±0.20 |
脾 | 2.20±0.26 | 0.22±0.03 | 0.12±0.04 | 0.08±0.01 |
胰 | 1.96±0.15 | 0.15±0.01 | 0.08±0.02 | 0.04±0.00 |
肝 | 2.43±0.27 | 0.28±0.02 | 0.20±0.02 | 0.19±0.01 |
皮肤 | 2.62±0.11 | 0.49±0.04 | 0.15±0.01 | 0.09±0.01 |
脑 | 0.22±0.00 | 0.02±0.00 | 0.01±0.00 | 0.01±0.01 |
骨 | 8.62±0.23 | 16.8±1.66 | 14.4±3.01 | 16.7±1.12 |
i.放射性示踪剂:[68Ga]1g
j.放射性示踪剂:[68Ga]1h
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 9.69±1.49 | 0.45±0.07 | 0.11±0.05 | 0.04±0.01 |
心脏 | 3.10±0.35 | 0.24±0.12 | 0.08±0.01 | 0.05±0.01 |
肌肉 | 1.92±0.14 | 0.14±0.04 | 0.05±0.01 | 0.03±0.00 |
肺 | 4.35±0.52 | 0.31±0.05 | 0.14±0.03 | 0.10±0.01 |
肾 | 18.2±1.65 | 2.07±0.62 | 1.13±0.08 | 1.67±0.54 |
脾 | 1.91±0.48 | 0.13±0.03 | 0.07±0.01 | 0.07±0.01 |
胰 | 1.48±0.27 | 0.09±0.03 | 0.05±0.02 | 0.04±0.01 |
肝 | 1.99±0.29 | 0.15±0.05 | 0.07±0.01 | 0.09±0.04 |
皮肤 | 2.31±0.25 | 0.39±0.13 | 0.11±0.02 | 0.07±0.01 |
脑 | 0.24±0.03 | 0.02±0.01 | 0.01±0.00 | 0.01±0.01 |
骨 | 8.31±0.84 | 12.1±0.84 | 11.9±1.31 | 12.0±0.82 |
k.放射性示踪剂:[177Lu]1h
0.5小时 | 1小时 | 6小时 | 24小时 | |
血液 | 0.54±0.11 | 0.12±0.02 | 0.016±0.007 | 0.003±0.001 |
心脏 | 0.23±0.05 | 0.08±0.02 | 0.024±0.005 | 0.014±0.003 |
肌肉 | 0.39±0.24 | 0.06±0.01 | 0.031±0.011 | 0.021±0.005 |
肺 | 1.35±1.52 | 0.20±0.05 | 0.062±0.006 | 0.040±0.003 |
肾 | 1.21±0.94 | 1.48±0.60 | 0.686±0.191 | 0.411±0.125 |
脾 | 0.15±0.04 | 0.07±0.01 | 0.038±0.005 | 0.034±0.005 |
胰 | 0.15±0.03 | 0.07±0.02 | 0.021±0.001 | 0.013±0.005 |
肝 | 0.20±0.03 | 0.13±0.03 | 0.088±0.021 | 0.068±0.013 |
皮肤 | 0.41±0.12 | 0.11±0.03 | 0.052±0.006 | 0.042±0.008 |
脑 | 0.03±0.01 | 0.01±0.00 | 0.003±0.003 | 0.014±0.016 |
骨 | 12.4±1.19 | 11.4±0.31 | 12.7±0.90 | 11.6±1.14 |
l.放射性示踪剂:[68Ga]2
m.放射性示踪剂:[68Ga]3
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 8.33±0.23 | 1.92±0.15 | 0.70±0.13 | 0.37±0.07 |
心脏 | 3.45±0.25 | 2.02±0.97 | 1.16±0.13 | 1.05±0.11 |
肌肉 | 1.62±0.47 | 0.68±0.09 | 0.57±0.14 | 0.28±0.04 |
肺 | 71.6±6.33 | 15.6±1.39 | 41.3±5.15 | 34.8±1.90 |
肾 | 12.2±1.51 | 17.1±0.70 | 7.99±1.08 | 8.99±0.20 |
脾 | 12.8±4.35 | 8.33±2.22 | 10.3±2.65 | 15.7±1.59 |
胰 | 1.73±0.08 | 1.07±1.04 | 0.26±0.02 | 0.25±0.03 |
肝 | 19.7±1.05 | 9.86±0.66 | 23.5±3.13 | 25.4±2.80 |
皮肤 | 1.24±0.01 | 1.10±0.18 | 0.41±0.02 | 0.33±0.06 |
脑 | 0.28±0.03 | 0.06±0.01 | 0.06±0.01 | 0.05±0.01 |
骨 | 4.17±0.35 | 9.26±1.45 | 9.26±1.13 | 10.6±0.85 |
n.放射性示踪剂:[68Ga]HBED-CC
2分钟 | 30分钟 | 60分钟 | 120分钟 | |
血液 | 7.66±0.75 | 0.83±0.09 | 0.14±0.04 | 0.01±0.00 |
心脏 | 2.74±0.34 | 0.34±0.06 | 0.17±0.11 | 0.09±0.00 |
肌肉 | 2.30±0.13 | 0.32±0.06 | 0.11±0.04 | 0.05±0.02 |
肺 | 4.27±0.34 | 0.58±0.07 | 0.19±0.04 | 0.07±0.02 |
肾 | 27.2±0.64 | 3.22±0.41 | 0.91±0.32 | 0.08±0.05 |
脾 | 1.69±0.18 | 0.26±0.04 | 0.12±0.02 | 0.13±0.03 |
胰 | 1.60±0.12 | 0.26±0.01 | 0.13±0.05 | 0.07±0.01 |
肝 | 1.75±0.08 | 0.38±0.08 | 0.11±0.02 | 0.04±0.02 |
皮肤 | 3.18±0.43 | 0.64±0.08 | 0.09±0.07 | 0.03±0.01 |
脑 | 0.29±0.08 | 0.04±0.01 | 0.02±0.01 | 0.02±0.00 |
骨 | 1.85±0.05 | 0.28±0.06 | 0.25±0.16 | 0.18±0.06 |
表5.在普通CD-1雄性小鼠中iv注射之后a)骨骼/血液比率和b)骨骼/肌肉比率的比较
a)骨骼/血液比率
b)骨骼/肌肉比率
a;注射后6小时,b;注射后24小时
治疗诊断剂,1h:[68Ga]1h和[177Lu]1h
1h,含有针对其它治疗用金属比如177Lu和90Y的DOTA螯合基团的衍生物,也制备为用于骨转移的放射性核素治疗剂。生物分布研究结果显示如表4j-k所示显示,[68Ga]1h和[177Lu]1h于iv注射后60分钟在普通小鼠中的骨摄取分别是11.9±1.3和11.4±0.3(%剂量/g)。[68Ga]1h和[177Lu]1h于iv注射后60分钟在普通小鼠中的骨骼/肌肉比率分别是233和200。[68Ga]1h和[177Lu]1h于iv注射后60分钟在普通小鼠中的骨骼/血液比率分别是112和97。两种放射性示踪剂也显示高羟基磷灰石结合(>90%)。[177Lu]1h展示优异的骨摄取、骨保留和快速肾分泌。在[68Ga]1h和[177Lu]1h之间并未观察到差异。含DOTA的试剂1h能够用作治疗诊断剂,用68Ga标记用于骨成像和在用177Lu或90Y标记的情况下用于缓和转移骨痛。
使用羟基磷灰石的体外结合研究
为了确认[68Ga]BPAMD,[68Ga]1a-h,2,和3以及[18F]NaF(阳性对照)与活性骨表面有关的结合,在模型系统中用羟基磷灰石聚集体测试这些化合物。使用预先形成的羟基磷灰石聚集体的体外结合研究显示的是,二膦酸盐/酯[68Ga]BPAMD、[68Ga]1a-h、2、和3以及[18F]NaF显示优异的体外结合(70-90%结合),如表6所示。正如期望,[68Ga]HBED-CC,一种不含二膦酸盐/酯基团的螯合剂,显示很低的羟基磷灰石聚集体体外结合(0.4±0.1%结合)。
表6.体外羟基磷灰石结合
放射性配体 | 羟基磷灰石结合(%) |
[18F]NaF | 78.4±3.9 |
[68Ga]BPAMD | 90.6±6.0 |
[68Ga]1a | 92.3±1.1 |
[68Ga]1b | 91.7±5.6 |
[68Ga]1c | 89.1±1.0 |
[68Ga]1d | 95.1±0.5 |
[68Ga]1e | 95.8±0.9 |
[68Ga]1f | 96.4±1.2 |
[68Ga]1g | 88.0±10.5 |
[68Ga]1h | 96.7±0.9 |
[177Lu]1h | 90.9±1.1 |
[68Ga]2 | 90.8±1.5 |
[68Ga]3 | 95.8±0.1 |
[68Ga]HBED-CC | 0.4±0.1 |
各值代表平均值±SD,n=2-4,重复三次。
小鼠的骨微-PET成像
小鼠中的微-PET成像研究用[18F]NaF(0.3mCi)、[68Ga]BPAMD(0.5mCi)和[68Ga]1a(0.5mCi)成功进行。于注射后60分钟进行图像采集15分钟。结果清楚地指出,全部试剂集中在小鼠脊柱中,如图1-3所示。尽管可能由于小鼠尺寸,脊椎的单独部分不是视觉上可分离的,68Ga标记的二膦酸盐/酯和[18F]NaF的骨摄取提供同样高骨摄取。新的骨成像剂[68Ga]1a可能适于用作骨成像剂,产生与对[18F]NaF先前报告的那些可比拟的图像(图1-3)。
两种HBED-CC-BP试剂[68Ga]1a和[68Ga]2显示优异的骨摄取和保留,其可与[18F]NaF比拟。与[18F]NaF类似,这些新的68Ga标记二膦酸盐/酯的摄取和保留机理可能与二膦酸盐/酯经由离子交换反应沉积在活性骨表面(羟基磷灰石)上有关。骨成像剂从肾经由肾小球过滤的清除速率将确定背景清除率,从而强烈影响信噪比。早先报告的是,氟阴离子显示肾中的高清除率和低重摄取,因此[18F]NaF显示最佳体内骨骼/背景比。新[68Ga]HBED二膦酸盐/酯[68Ga]1a-h和[68Ga]2可能具有骨摄取和保留机理的相同体内动力学。加入额外的氨基酸,2-葡糖胺,Glu-NH-CO-NH-Lys(Ahx)或DOTA官能团,1b-h并不显著改变普通小鼠中骨摄取和保留机理的体内动力学。
为了测试[68Ga]1g与骨(通过二膦酸盐/酯基团)和PSMA(通过Glu-NH-CO-NH-Lys(Ahx)基团)受体的选择性结合,小鼠中的体内生物分布显示高骨摄取,其类似[68Ga]1a和[68Ga]2(表4)。此外,[68Ga]1g展示高肾摄取和保留,原因是肾也是表达高水平PSMA受体的器官(表4-i)。小鼠中的生物分布数据支持的概念是,[68Ga]1g靶向骨和PSMA结合位点两者。还用PSMA阳性LNCaP细胞和PSMA阴性PC3细胞进行体外结合研究。观察到的是,[68Ga]1g仅在LNCaP细胞过表达PSMA结合位点展示高细胞摄取和保留,这意味着[68Ga]1g向这些细胞的结合是选择性结合至细胞膜上的PSMA受体(图4和5)。
在携带PSMA表达性肿瘤的小鼠中的[68Ga]1g微-PET成像
新探针[68Ga]1g被发明用于靶向骨转移和主动生长中的过表达PSMA的肿瘤两者。小鼠中的微PET图像支持的概念是,[68Ga]1g靶向骨和PSMA结合位点两者,如图6所示。
虽然某些实施方式已有说明和描述,应理解能够按照本领域普通技术对其进行变化和修饰,而不背离如所附权利要求中所定义的技术。
本公开并不受本申请中描述的特别实施方式限制。能够进行修饰和变化而不背离其主旨和范围,其对本领域技术人员来说是明显的。基于本文的描述,除了本文枚举的那些之外,在公开范围内的功能上等价的方法和组合物也对本领域技术人员来说是明显的。所述修饰和变化期望属于所附权利要求的范围。本公开仅受所附权利要求限制,还包括所述权利要求所能等价的完整范围。应理解,本公开并不局限于特别的方法、试剂、化合物组合物或生物学系统,其当然能够变化。还应理解,本文所用的术语仅意在描述特别实施方式,并非意在限制。
本说明书提及的全部出版物、专利申请、颁布的专利和其它文献通过援引并入本文,正如各单独的出版物、专利申请、颁布的专利或其它文献被特别且单独地指出通过援引全部加入。如果通过援引加入的文本中的定义与本公开中的定义矛盾,则加以排除。
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Claims (29)
1.根据式I的化合物:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
n是1至8;
Y独立地是CH或N;
R1是氢或(C1-C6)烷基;
R2,R5和R8独立地是氢或羧酸保护基团;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R6是氢或(C1-C6)酰基;和
R7是氨基酸的α-位取代基,和
R8独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基,芳基烷基和杂芳基。
2.权利要求1的化合物,其中
A是(CH2)m,其中m是0、1、2或3;
R1是Et;
X选自:
n是1至8;
R2,R5和R8是叔-Bu;
R6是AcO;和
B,Y,R3,R4和R7如权利要求1中所定义。
3.权利要求1的化合物,其中
A是CH2;
Y是CH;
R7选自氢,甲基,-CH2COOR8和-(CH2)2COOR8;
R1,R2,R3,R4,R5,R6和R8是氢。
4.权利要求1至3中任一项的化合物,其中
X是
5.权利要求1至3中任一项的化合物,其中
X是
6.权利要求1至3中任一项的化合物,其中
X是
7.权利要求1至3中任一项的化合物,其中
X是
8.权利要求1至3中任一项的化合物,其中
X是
和n是1至8。
9.权利要求1的化合物,具有下述结构:
10.权利要求1的化合物,具有下述结构:
11.权利要求1的化合物,具有下述结构:
12.一种配合物,包含螯合至金属M或其药学上可接受的盐的权利要求1的化合物,其中M选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb和51Cr。
13.权利要求12的配合物,具有根据式II的结构:
或其药学上可接受的盐,
其中
A是在链、环或其组合中包含1至10个碳原子的二价连接部分,其中至少一个碳原子任选用O,-NR9-或-C(O)-替换;
B是CR3R4;
X选自:
n是1至8;
Y独立地是CH或N;
R3和R4独立地是氢,(C1-C10)烷基,乙二醇基或丙二醇基;
R5和R8独立地是氢或羧酸保护基团;
R6是(C1-C6)酰基;
R7是氨基酸的α-位取代基;
R8独立地选自H,烷基,环烷基,杂环烷基,芳基,烷基芳基,芳基烷基和杂芳基;和
M是选自44Sc,47Sc,203Pb,67Ga,68Ga,72As,111In,90Y,97Ru,62Cu,64Cu,52Fe,52mMn,140La,175Yb,153Sm,166Ho,149Pm,177Lu,142Pr,159Gd,213Bi,67Cu,111Ag,199Au,161Tb,和51Cr的金属。
14.权利要求13的配合物,其中
A是(CH2)m,其中m是0、1、2或3;
X选自:
n,Y,R3,R4,R5,R6,R7和R8如权利要求13中所定义。
15.权利要求13的配合物,其中
A是CH2;
Y是CH;
R7选自氢,甲基,-CH2COOR8和-(CH2)2COOR8;
R3,R4,R5,R6和R8是氢。
16.权利要求13至15中任一项的配合物,其中
X是
17.权利要求13至15中任一项的配合物,其中
X是
18.权利要求13至15中任一项的配合物,其中
X是
19.权利要求13至15中任一项的配合物,其中
X是
和n是1至8。
20.权利要求12至15中任一项的配合物,其中M是68Ga。
21.权利要求13的配合物,具有下述结构:
22.权利要求13的配合物,具有下述结构:
23.权利要求13的配合物,具有下述结构:
24.权利要求13的配合物,具有下述结构:
其中n是1至8。
25.权利要求12的配合物,具有下述结构:
其中n是1至8。
26.一种药物组合物,包含药学上可接受的载体和根据权利要求1-25中任一项的化合物或配合物或其药学上可接受的盐。
27.一种体内成像的方法,包括将有效量的根据权利要求12-25中任一项的配合物给予至受试者,并检测化合物在所述受试者中的放射性谱。
28.在受试者中治疗一种或多种骨肿瘤的方法,包括给予有效量的权利要求12的配合物,其中
X是
和n是1至8。
29.一种包括无菌容器的试剂盒,所述无菌容器含有有效量的权利要求1-11中任一项的化合物或其药学上可接受的盐,和用于治疗用途的指导书。
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EP3958916A4 (en) * | 2019-04-26 | 2023-08-09 | Five Eleven Pharma Inc. | PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITORS AS DIAGNOSTIC AND RADIONUCLID-THERAPEUTIC AGENTS |
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