CN114981279A - 新型钆基化合物、其制备方法及含有其的mri造影剂 - Google Patents
新型钆基化合物、其制备方法及含有其的mri造影剂 Download PDFInfo
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- CN114981279A CN114981279A CN202180010711.5A CN202180010711A CN114981279A CN 114981279 A CN114981279 A CN 114981279A CN 202180010711 A CN202180010711 A CN 202180010711A CN 114981279 A CN114981279 A CN 114981279A
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- 229910052688 Gadolinium Inorganic materials 0.000 title claims abstract description 33
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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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
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- A—HUMAN NECESSITIES
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- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明涉及一种具有钆络合物和阿魏酸通过连接基团结合的结构的新型钆基化合物、其的制备方法以及含有其的MRI造影剂。
Description
技术领域
本发明涉及一种新型钆基化合物、其的制备方法以及含有其的MRI造影剂。具体地,本发明涉及具有钆络合物和阿魏酸(ferulic acid)通过连接基团结合的结构的新型钆基化合物、其的制造方法以及含有其的MRI造影剂。
背景技术
当今,由于人口老龄化,患有退行性脑病的患者日益增加,因此,迫切需要对疾病早期发现。作为退行性脑疾病,有帕金森病、血管性痴呆、阿尔茨海默病等,作为导致这些疾病的原因之一,可以考虑因β淀粉样蛋白聚合物(oligomeric Aβ)的过度积累而引起的神经毒性。
β淀粉样蛋白(Aβ)是在阿尔茨海默病患者的大脑中发现的淀粉样蛋白斑的主要成分,是指对阿尔茨海默病做决定性作用的36至43个氨基酸肽。该肽来源于淀粉样前体蛋白(APP)。
所述β淀粉样蛋白分子可以聚集形成可以多种形式存在的可溶性聚合物,并且,众所周知,所形成的β淀粉样蛋白聚合物(oligomeric Aβ)对神经细胞有毒,因此,在大脑中过度积累的同时,直接参与阿尔茨海默病的发病。由此预测通过检测β淀粉样蛋白聚合物浓度的变化,将可以早期诊断退行性脑疾病。
另一方面,磁共振成像(Magnetic Resonance Image,以下,MRI)是一种利用身体组织之间氢原子分布不同且在磁场中氢原子弛豫的现象来获得身体的解剖学、生理学、生化学信息图像的方法。MRI与CT或PET不同,不使用对人体有害的辐射,而是利用强磁场下的磁场梯度和无线电波在体内产生图像,从而,无创、分辨率高、非常适合软组织检查。
为了更加精密地利用MRI设备,向对象注入造影剂(contrast agent)来得到MRI图像。MRI图像上各组织之间的对照图(contrast)是因为组织内水分子的原子核自旋向平衡状态恢复的弛豫(relaxation)作用不同而产生的现象。造影剂使用顺磁性或超顺磁性材料来影响弛豫作用,以加大组织之间的弛豫度差异,引发MRI信号的变化,而起到使组织之间的对照更加清晰的作用。
目前,临床上最常用的造影剂是,基于钆(Gd)螯合物的造影剂。目前使用Gd-DTPA(马根维显(Magnevist))、Gd-DOTA(多它灵(Dotaram))、Gd(DTPA-BMA)(欧乃影(Omniscan))、Gd(DO3A-HP)(钆特醇(ProHance))、Gd(BOPTA)(莫迪司(MultiHance))等。然而,大多数市售造影剂是分布在细胞外空间(extracellular fluide,ECF)中的非特异性造影剂。作为特异性造影剂,特别地仅使用肝脏特异性造影剂。最近的研究虽然促进了通过具有特异性靶向或生理活性(pH变化、酶活性)可以表现出信号增强的造影剂的开发,但是对退行性脑病的特异性MRI造影剂尚未获得足够的结果。
发明内容
本发明的目的在于,提供一种钆基化合物,所述钆基化合物可用作MRI造影材料,尤其,对退行性脑病具有特异性。
本发明的其他目的在于,提供一种含有所述化合物的MRI造影剂。
本发明的其他另一目的在于,提供一种所述化合物的制备方法。
根据本发明,提供一种钆基化合物,其中,由以下化学式1表示。
[化学式1]
在所述化学式1中,
A表示*-(CH2)n-A1-*,
n表示0至5中的任一整数,
A1表示*-COO-*、*-CO-*、*-NH-*、*-CH2-*、*-CONH-*或*-O-*,
连接基团表示*-L1-NHCO-L2-*、*-L1-O-R-O-L2-*、*-L1-CH2-L2-*、*-L1-NH-L2-*,或者*-L1-COO-L2-*,
L1表示直链或支链(C1-C30)烷基,
L2表示单键,或直链或支链(C1-C30)烷基,
R表示直链或支链(C1-C20)烷基,
Fa表示化学式2:
[化学式2]
*表示连接位点。
而且,根据本发明,提供一种MRI造影剂,其含有由所述化学式1表示的钆基化合物。
而且,根据本发明,提供一种包括以下步骤的由所述化学式1表示的钆基化合物的制备方法,所述步骤,包括:
(a)使以下化学式1-1的化合物与化学式1-2的化合物反应得到以下化学式1-3的化合物的步骤;
[化学式1-1]
在所述化学式1-1中,
L2如上化学式1中所定义,
[化学式1-2]
[化学式1-3]
在所述化学式1-2及1-3中,
PT表示保护基团,
连接基团表示*-L1-NH-L2-*,
L1、L2、A及Fa如上化学式1中所定义,
(b)从所述化学式1-3的化合物中去除保护基团PT的步骤;以及
(c)将在所述步骤(b)中得到的化合物与钆水合物反应得到化学式1的化合物的步骤。
发明效果
根据本发明的新型钆基化合物,由于具有足够的自弛豫特性,不仅可以用作MRI造影材料,还可以与β-淀粉样蛋白聚合物(oligomeric Aβ)结合,在β淀粉样蛋白聚合物的存在下得到MRI造影增强效果,从而,可以用于与β淀粉样蛋白聚合物相关的疾病的诊断,特别是退行性脑病的诊断。
附图说明
图1a为根据本发明的化合物的制备例中制备的化合物L的1H NMR谱图。
图1b为根据本发明的化合物的制备例中制备的化合物L的13C NMR谱图。
图1c为根据本发明的化合物的制备例中制备的化合物L的HR-MS谱图。
图1d为根据本发明的化合物的制备例中制备的化合物L的HPLC色谱图。
图2a为根据本发明的化合物的制备例中制备的GdL的HR-MS谱图。
图2b为根据本发明的化合物的制备例中制备的GdL的HPLC色谱图。
图3表示根据本发明的GdL的自弛豫率(r1、r2)分析图表。
图4表示根据本发明的GdL和各种市售造影剂(加乐显(Gadovist)、多它灵(Dotarem)、钆特醇(Prohance)、马根维显(Magnevist)、普美显(Primovist)、欧乃影(Omniscan)、莫迪司(Multihance))的动力学稳定性的图。
图5是表示MRI体模样本的MR T1体膜的MR信号强度的比较图表。
具体实施方式
下面,本申请中使用的术语仅用于说明特定实施例,并不用于限制本发明。除非另有定义,在本说明书中使用的所有术语,包括技术或科学术语,与本发明所属领域的普通技术人员通常理解的含义相同。诸如常用词典中定义的术语应解释为与相关技术上下文中的含义一致的含义,除非在本申请中明确定义,不得解释为理想或过于形式化的含义。
根据本发明的钆基化合物,可以由以下化学式1表示。
[化学式1]
在所述化学式1中,
A表示*-(CH2)n-A1-*,
n表示0至5中的任一整数,具体地,可以表示1至5中的任一整数,更具体地,可以为1至3中的任一整数,
A1表示*-COO-*、*-CO-*、*-NH-*、*-CH2-*、*-CONH-*、或*-O-*,具体地,可以表示*-CONH-*,
连接基团表示*-L1-NHCO-L2-*、*-L1-O-R-O-L2-*、*-L1-CH2-L2-*、*-L1-NH-L2-*、或*-L1-COO-L2-*,具体地,可以表示*-L1-NH-L2-*,
L1表示直链或支链(C1-C30)烷基,具体地,L1可以为直链或支链(C1-C10)烷基,更具体地,可以为直链或支链(C1-C5)烷基,
L2表示单键,或直链或支链(C1-C30)烷基,具体地,可以为单键,R表示直链或支链(C1-C20)烷基,具体地,可以表示直链或支链(C1-C10)烷基,更具体地,可以表示直链或支链(C1-C5)烷基,
Fa表示化学式2:
[化学式2]
*表示连接位点。
根据本发明的一实现例,在所述化学式1中,n可以表示1至5的任一整数,A1可以表示*-CONH-*。
根据本发明的其他实现例,L1可以表示直链或支链(C1-C10)烷基,L2可以表示单键。
在所述化学式1的钆基化合物中,钆可以与至少一个水分子配位。例如,在所述化学式1的钆基化合物中,钆可以与一个或两个水分子配位。
在本发明的所述化学式1的钆基化合物中,当A1为*-COO-*、*-CO-*、或*-CONH-*时,氧原子可以与钆形成配位键。
本发明的化学式2是衍生自阿魏酸(Gallic acid)的部分。据报告阿魏酸是存在于植物细胞壁中的酚类化学物质,对来自氧分子的各种活性氧具有很高的抗氧化活性,对铁离子、铜离子等氧化性过渡金属有很强的抗氧化效果。因此,阿魏酸一直被用作抗衰老剂、疾病治疗剂的主要成分,但迄今为止尚未考虑将其用作具有β淀粉样蛋白聚合物(oligomeric Aβ)靶向功能的MRI造影剂。
如后述的实施例所示,本发明的所述化学式1的钆基化合物可以特异性结合于哺乳动物的β淀粉样蛋白聚合物(oligomeric Aβ)。
此外,由于本发明的所述化合物具有水溶性,与至少一个水分子配位而具有自弛豫特性,因此,可以通过增加体内至少一个水分子和氢原子的弛豫率来提高图像对比度,由此可以用作MRI造影材料。
因此,根据本发明,提供一种MRI造影剂,其含有由所述化学式1表示的钆基化合物。此外,由于本发明的化合物可以与β淀粉样蛋白聚合物(oligomeric Aβ)结合,因此,本发明的MRI造影剂,具体地可用于与β淀粉样蛋白聚合物(oligomeric Aβ)相关的疾病,更具体地,可用于诊断退行性脑病,例如,帕金森病、血管性痴呆、阿尔茨海默病等的退行性疾病。因此,根据本发明的一实现例,可以提供一种用于诊断退行性脑病的特异性MRI造影剂,其含有所述化学式1的化合物。进而,如上所述,据最新研究,确认到由淀粉样前体蛋白诱导的淀粉样β聚合物(oligomeric Aβ)在脑中过度积累,并参与阿尔茨海默病的发病。因此,含有靶向β淀粉样蛋白聚合物的本发明的化合物的MRI造影剂,可以成为用于早期诊断阿尔茨海默病的特异性MRI造影剂。
根据本发明的所述化学式1的钆基化合物,可以通过包括以下步骤的方法而制备:
(a)使以下化学式1-1的化合物与化学式1-2的化合物反应得到以下化学式1-3的化合物的步骤;
(b)从所述化学式1-3的化合物中去除保护基团PT的步骤;以及
(c)将在所述步骤(b)中得到的化合物与钆水合物反应得到化学式1的化合物的步骤。
[化学式1-1]
在所述化学式1-1中,
L2如上化学式1中所定义,
[化学式1-2]
[化学式1-3]
在所述化学式1-2及1-3中,
PT表示保护基团,
连接基团表示*-L1-NH-L2-*,
L1、L2、A及Fa如上化学式1中所定义。
根据本发明的一实现例,在所述步骤(a)中,所述L2可以是单键。
必要时,可以在进行所述步骤(a)之前,对在所述化学式1-1中与苯环直接连接的-OH基,利用通常用于-OH的保护基团基,例如乙酰基、苯甲酰基、甲氧基甲基醚、甲硫基甲醚等进行保护,在对所述-OH基保护好后进行所述步骤(a)。另外,必要时,可以在进行步骤(a)之前,使用卤素化合物,用卤素取代在所述化学式1-1中与L2直接连接的-OH基,可以在所述卤化之后,进行所述步骤(a)。
在所述化学式1-2及1-3中,PT表示保护基团,通常用于保护-OH基而使用的保护基团,例如,可以举甲基、苄基、叔丁基等。
所述步骤(b)是去除保护基团的步骤,所述保护基团,即PT可以通过本领域常用的方法去除,例如,可以使用碱水溶液或酸水溶液。
下面,为了详细理解本发明,举例本发明的代表化合物,说明根据本发明的化合物,其的制备方法以及含有其的MRI造影剂的特性。
1.根据本发明的化合物的制备例
1)三叔丁基2,2`,2``-(10-(2-((2-(3-(3-羟基-4-甲氧基苯基)丙烯酰胺)乙基)
氨基)-2-氧代乙基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基)三乙酸酯(化合物1)的合成
将阿魏酸(0.2g,1.03mmol)、N,N-二异丙基乙胺(0.26mL,2.06mmol)及羟基苯并三唑(Hydroxybenzotriazole,HOBt)(0.24g,1.54mmol)溶解于二甲基甲酰胺(DMF)(10mL)中,并搅拌30分钟。
然后,将2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HBTU)(0.78g,2.06mmol)及DO3A-NH2(0.64g,1.03mmol)添加到所述混合物中,并在室温下搅拌20小时。
添加10%酸氢钠之后停止反应,并用乙酸乙酯(3×50mL)进行提取。将得到的有机层用盐水(brine solution)洗涤后,添加硫酸钠去除残留的水分,在真空下进行干燥,得到油状物质(化合物1)。(收率:0.72g(89%))
所得化合物1的HR-FAB-MS分析结果为如下。
HR-FAB-MS calculated for C40H66N6NaO10(m/z):813.4738[M+Na]+;found,813.4743[M+Na]+
2)(E)-2,2`,2``-(10-(2-((2-(3-(3-羟基-4-甲氧基苯基)丙烯酰胺)乙基)氨
基)-2-氧代乙基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基)三乙酸酯(化合物L)的合成
将所述化合物1(0.7g,0.89mmol)在冰浴(ice-bath)中溶解于三氟乙酸(TFA)和二氯甲烷(CH2Cl2)的混合溶液中,然后,在室温搅拌至完全溶解并变为透明,在搅拌的同时,利用TLC确认反应物是否反应。反应充分进行后,去除溶剂,添加乙醚,得到沉淀物。然后,过滤沉淀物,用乙醚洗涤数次后,进行真空干燥,得到淡黄白色的固体(化合物L)。
所得化合物L的1H NMR谱、13C NMR谱、HR-MS谱及HPLC色谱分别示于图1a至1d中。(收率:0.48g(87%))
1H NMR(500MHz,MeOD);d=7.43(d,J=15.7Hz,1H),7.19(d,J=1.6Hz,1H),7.06(dd,J=8.2,1.7Hz,1H),6.80(d,J=8.2Hz,1H),6.69(d,J=15.7Hz,1H),3.89(s,3H),3.88-3.82(m,4H),3.72-3.34(m,16H),3.20-3.06(m,8H).
13C NMR(126MHz,MeOD);d=169.73,163.16,162.88,149.92,149.41,142.04,128.48,123.57,119.56,116.59,111.87,56.64,56.17,51.92,50.90,50.31,40.61,39.63.
HR-MS calculated for C28H43N6O10(m/z):623.3041[M+H]+;found,623.3042[M+H]+
使用分析用HPLC进行纯度分析:96.04%
3)化合物GdL(本发明化合物)的合成
将化合物L(0.4g,0.64mmol)溶解在蒸馏水(10mL)中,使用1M氢氧化钠溶液将pH调节至7后,添加在蒸馏水(5mL)中溶解的Gd(Cl)3·H2O(0.24g,0.64mmol)。此后,在室温下搅拌1天,搅拌期间的pH保持在7至7.3。搅拌结束后,将过滤得到的物质利用高效液相色谱法(HPLC)进一步纯化,得到化合物GdL。
所得化合物GdL的HR-MS谱和HPLC色谱分别示于图2a及2b。(收率:0.15g(31%))
HR-MS calculated for C28H40GdN6O10(m/z):778.2047[M+H]+;found,778.2044[M+H]+
使用分析用HPLC进行纯度分析:96.69%
下面,可以使用所制备的本发明的代表化合物,用作MRI造影物质,与此同时进行了特性评价以确定β淀粉样蛋白聚合物是否具有靶向能力。
2.本发明化合物的特性评价方法及结果
1)自弛豫率(Relaxivity)的测量
在三蒸水中,将通过所述方法合成的GdL稀释至各种浓度(0.0625、0.125、0.25、0.5、1mM)制备体模,然后在3T MRI中测量T1、T2弛豫时间(Relaxation time)。由此计算出各浓度的R(弛豫率=1/T),通过线性回归分析得到合成的GdL的自弛豫率(r1,r2)结果。(参照图3)
如图3所示,测量到GdL的r1值为3.73±0.10,r2值为5.29±0.10,由此确认到该自弛豫率是本发明的造影剂充分用于临床的值,合成的GDL可以用作MRI造影剂。
2)动力学稳定性(Kinetic stability)评价
将GdL与几种市售造影剂(加乐显(Gadovist)、多它灵(Dotarem)、钆特醇(Prohance)、马根维显(Magnevist)、普美显(Primovist)、欧乃影(Omniscan)、莫迪司(Multihance))在PBS(pH 7.4)中制备2.5mM溶液之后,每当量添加250mM的氯化锌(ZnCl2),来评价钆络合物的配体-金属结合稳定性,将其结果示于图4中。这可以测量锌离子对钆离子的金属转移(Transmetallation)作为自弛豫率的变化来确认。
已知线性结构的钆络合物与环状结构相比稳定性较差。参考图4,可以确认合成的GdL具有比线性造影剂更高的稳定性,并且表现出与环状市售造影剂相似的变化率,并具有优异的稳定性。
3)用于确认β淀粉样蛋白聚合物靶向的体模实验方法
将HFIP(221.5μl)添加到β淀粉样蛋白(1mg,1mM)中,并在室温下使用振荡器振荡1小时,去除预聚集(Preaggregation)。
接着,在空气中干燥已去除预聚集的β淀粉样蛋白,加入DMSO(221.5μl),将浓度调节至1mM,然后使用混合器和超声波器形成悬浮液,然后添加PBS(1X,pH 7.4,878.5μl),将浓度调节至0.2mM。
然后,在37℃的温度下,使用振荡器培养4天后,将已聚合的β淀粉样蛋白聚合物(oligomeric Aβ)分别分配200μl,并将以2mM的浓度溶解在PBS的化合物GdL和市售造影剂分别添加20μl,然后使用振荡器在37℃的温度下培养24小时。
结束培养24小时后,离心去除上清液,然后用PBS洗涤β淀粉样蛋白聚合物,向颗粒(Pellet)中添加200μl的PBS:DMSO=9:1溶液,制备MRI体模样品。
4)实验结果
β淀粉样蛋白聚合物靶向实验在9.4T MR设备进行,将其结果示于图5中。图5示出MRI体模样本的MR T1体膜的MR信号强度的比较图表。
参考图5,可知仅培养β淀粉样蛋白聚合物的体模(对照组(control))和一起培养市售造影剂的体模(比较例),在造影增强效果方面显示出相似的效果。由此,可以确认用于比较例的市售造影剂对β淀粉样蛋白聚合物几乎没有靶向效果。
另一方面,一起培养作为本发明的化合物的GDL的体模与使用对照组和市售造影剂的比较例相比,显示出显著高的造影增强效果。由此,可以确认本发明的化合物对β淀粉样蛋白聚合物具有靶向效果,并且,可知本发明的GdL适合用作β淀粉样蛋白聚合物靶向造影剂。
尽管以上参照本发明的优选实施例进行了说明,但应理解本领域的普通技术人员在不脱离权利要求范围中记载的本发明的精神和范围的情况下,可以对本发明进行各种修改及变更。
Claims (10)
2.根据权利要求1所述的钆基化合物,其特征在于,n表示1至5的任一整数,A1表示*-CONH-*。
3.根据权利要求1所述的钆基化合物,其特征在于,L1表示直链或支链(C1-C10)烷基,L2表示单键。
4.根据权利要求1所述的钆基化合物,其特征在于,所述钆与至少1个水分子配位。
5.根据权利要求1所述的钆基化合物,其特征在于,与哺乳动物的β淀粉样蛋白聚合物特异性结合。
6.一种MRI造影剂,其特征在于,其含有根据权利要求1所述的钆基化合物。
7.根据权利要求6所述的MRI造影剂,其特征在于,其用于退行性脑病的诊断。
8.根据权利要求7所述的MRI造影剂,其特征在于,其用于阿尔茨海默病的诊断。
10.根据权利要求9所述的方法,其特征在于,所述步骤(a)中,所述L2为单键。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020127629A1 (en) * | 2000-10-19 | 2002-09-12 | Alexei Bogdanov | Imaging of enzymatic activity |
US20160251378A1 (en) * | 2015-02-27 | 2016-09-01 | Rochester Institute Of Technology | Transmetalation Methods for the Synthesis of PET and SPECT Imaging Agents |
US20190292206A1 (en) * | 2018-03-22 | 2019-09-26 | Kyungpook National University Industry-Academic Cooperation Foundation | Gadolinium complex, method for synthesis of the gadolinium complex, and mri contrast agent including the gadolinium complex |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020127629A1 (en) * | 2000-10-19 | 2002-09-12 | Alexei Bogdanov | Imaging of enzymatic activity |
US20160251378A1 (en) * | 2015-02-27 | 2016-09-01 | Rochester Institute Of Technology | Transmetalation Methods for the Synthesis of PET and SPECT Imaging Agents |
US20190292206A1 (en) * | 2018-03-22 | 2019-09-26 | Kyungpook National University Industry-Academic Cooperation Foundation | Gadolinium complex, method for synthesis of the gadolinium complex, and mri contrast agent including the gadolinium complex |
Non-Patent Citations (2)
Title |
---|
ALEXEI BOGDANOV ET AL.: "Oligomerization of Paramagnetic Substrates Result in Signal Amplification and can be Used for MR Imaging of Molecular Targets", MOLECULAR IMAGINE, vol. 1, no. 1, pages 16 - 23, XP008022542, DOI: 10.1162/153535002753395671 * |
PAUL J. ENDRES ET AL.: "DNA-TiO 2 Nanoconjugates Labeled with Magnetic Resonance Contrast Agents", JOURNAL OF THE AMERICAN CHEMISTRY, vol. 129, pages 15760 - 15761, XP055830967, DOI: 10.1021/ja0772389 * |
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