CN1237911A - 用于通过近红外辐射(nir-辐射)诊断神经变性疾病的光学诊断剂 - Google Patents
用于通过近红外辐射(nir-辐射)诊断神经变性疾病的光学诊断剂 Download PDFInfo
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- CN1237911A CN1237911A CN97199895A CN97199895A CN1237911A CN 1237911 A CN1237911 A CN 1237911A CN 97199895 A CN97199895 A CN 97199895A CN 97199895 A CN97199895 A CN 97199895A CN 1237911 A CN1237911 A CN 1237911A
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Abstract
本发明涉及通式Ⅰ的化合物:Fm (-A1)(-Bn)(-Wo)(Ⅰ),其中:F是染料信号分子,其至少在600—1200nm的范围内具有最大吸收;A是结合β-淀粉样蛋白斑的生物分子;B是结合β-淀粉样蛋白斑的染料;W是结合β-淀粉样蛋白斑的、亲水性的低分子结构单元。本发明还涉及这些化合物通过近红外辐射(NIR辐射)体内和体外诊断神经变性疾病如阿尔茨海默氏病的应用,其是在NIR范围内作为荧光和透照诊断的显影剂。还涉及包含所述化合物的诊断剂。
Description
本发明涉及通过近红外辐射(NIR-辐射)在体内和体外诊断神经变性疾病的化合物,该化合物作为光学诊断剂的应用,以及包含这些化合物的诊断剂。
阿尔茨海默氏病(AD)是老年晚期痴呆中最常见的形式。AD的发病频率随着患者的年龄增大而提高,在85-90岁的年龄组中达到40-50%的值。AD只能在死后通过尸体解剖检查患者大脑来得到确诊。阿尔茨海默氏病患者的大脑在神经元组织中有多个特征性淀粉样蛋白斑,而且在血管周围,包围着营养不良的轴突和神经原纤维“结“。阿尔茨海默氏病患者的大脑还表现为仅有少量的突触。在该疾病的晚期时,还可进一步形成神经元结构的变性以及脑容量的明显减小(Wiesniewski,H.M.,Weigel,J.,Alzheimer’s disease neuropathology.Current status of interpretation of lesion development.Ann NY Acad Sci1992,673:270-84)。
淀粉样蛋白斑也称为淀粉样蛋白-β-肽(Aβ),其是一个由40-42个氨基酸组成的β-淀粉样蛋白前导蛋白(APP)片段(Master,C.L.,Simms,G.,Weinman,NA.等人,Amyloid plaque core protein in Alzheimerdisease and Down syndrome.Proc Natl Acad Sci USA 1985,82:4245-09;Kang,J.Lemaire,H.G.,Unterbeck,A.等人,The precursor ofAlzheimer’s disease amyloid A4 protein resembles a cell-surface receptor,Nature 1987,325:733-6)。蛋白斑的数量不与晚期痴呆的程度有相关关系,但对于阿尔茨海默氏病是一种较早且可靠的诊断剂。其假设是,AD产生不久后首先发生Aβ的积聚,然后才产生第一个临床症状(Hardy,L.,Allsop,D.,Amyloid deposition as the central event in theaetiology of Alzheimer’s disease,Trends Pharmacol Sci 1991,12:383-8)。
如果能有在患者死亡之前尽早地定量检测淀粉样蛋白斑的方法,其将对进一步研究AD产生重大影响,而且为治疗AD提供新的有效方法。
目前,还没有直接检测在AD患者大脑中淀粉样蛋白斑的方法。现在,AD的程度还仅是间接地通过脑体积或脑受损区域内的代谢紊乱(MRT和PET)来诊断。但该方法的重大缺陷是仅是间接检测AD,而其结果经常有非常高的统计学上的误差。因此,该方法的检测灵敏性与淀粉样蛋白斑的直接检测相比就低得多。
已知有许多方法用波长范围在600-1200nm的长波长光来透射和成象诊断生理组织(近红外诊断)。因为生理组织对上述光谱范围的长波长光具有相对高的透过性,除现代成象法如放射照相法、核磁共振成象法、或超声诊断法外,对于诊断人员近红外诊断已成为组织成象的另一种方法(Haller,E.B.,Time-resolved transillumination and opticaltomography,J Biomed Optics 1996,1:7-17)。用近红外辐射通过检测血红蛋白/脱氧血红蛋白来位置独立地记录婴儿脑中的血液流动和氧的生成程度是一种已知的方法,并已使用多年(Jobsis,F.F.,脑和心肌氧充足和循环参数的非侵入性红监测(Noninvasive infrared monitoring ofcerebral and myocardial oxygen sufficiency and circulatory parameters),Science 1977,198:1264-67;Chance,B.,Leigh,J.S.,Miyake,H.等人,Comparison of time-resolved and-unresolved measurements of deoxyglobinin brain,Proc Natl Acad Sci USA 1988,85:4971-75;Benaron DA.等人,Optical time-of-flight and absorbance imaging of biological media,Science1993,33:369A)。
近红外诊断不仅可以检测未被吸收的透射光,而且用近红外光辐射后发射的荧光辐射还可提供组织特异性信息。
用近红外辐射的主要问题是光线散射过强,使得足够清晰的物体以及该物体周围的不同光物理性质差异变得不明显。随着物体与表面的距离增加,该问题则变得更加严重,而且被认为是透照和荧光辐射检查中的主要限制因素。
因此,本发明的目的是提供可避免现有技术之缺陷的新型化合物。
本发明的目的是通过以下通式Ⅰ的化合物及其药物学上可接受的盐来解决的:
Fm(-Al)(-Bn)(-Wo) (Ⅰ)其中:
F是染料信号分子,其至少在600-1200nm的范围内具有一个最大吸收,
A是结合β-淀粉样蛋白斑的生物分子,
B是结合β-淀粉样蛋白斑的染料,
W是结合β-淀粉样蛋白斑的、亲水性的低分子结构单元,
m是1或2的整数,或者当n和o是零时,其为3-20的整数,
l和n相互独立地是0、1、或2,
o是0、1、2、3、或4的整数,
其条件是,l、n和o的和大于等于1。
令人惊奇地发现,本发明的化合物可积聚、结合或者富集在淀粉样蛋白斑或者淀粉样蛋白斑的组成部分上,并由此使待检测区域中后者的吸收和荧光均匀且增高。
用NIR辐射体内检测β-淀粉样蛋白斑沉积需要染料作为显影剂,其在600-1200nm的波长范围内具有高吸收并产生荧光量子,而且选择性地结合累积的β-淀粉样蛋白斑。
聚次甲基型染料的吸收和荧光性质的特征是,在600-1200nm之间具有高摩尔吸收系数,而且产生足够的荧光量子。该类型的染料通常具有高的光稳定性。
出乎意料地发现,为提高正常组织和病态组织之间的差异,富集在病态组织中或者选择性地结合病理变化组织的组成部分而且具有特殊的吸收和发射性质的染料是合适的。
在本发明中令人惊奇地发现,通式Ⅰ之本发明化合物可结合β-淀粉样蛋白斑。检测由于染料吸收而导致的(散射)辐射光变化或者由激发辐射诱导的荧光,并提供真实的组织特异性信息,该信息即可作为光变化程度的证据。
根据本发明,用此等染料作为信号分子F,该分子共价键地与选择性地结合β-淀粉样蛋白斑的结构连接或者被此等结构取代。
根据本发明之通式Ⅰ的化合物是例如其中:
a)l和n是零,m是1,而o是1-4,或者
b)n和o是零,m是3-20,而1是1-2,或者
c)l和o是零,m是1-2,n是1-2,其条件是,n与m的和小于等于3。
通式Ⅰ之本发明化合物优选为,其中F是花青、Squarilium、Croconium、部花青、或Oxonol染料。
R1-R4以及R7-R10相互独立地是氟、氯、溴、碘原子或者是硝基或-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-OSO3E1、SO2NHE1、-E1,其中E1和E2相互独立地是氢,饱和或不饱和的、直链或支链的C1-C50烷基链,该链或部分该链可选择性地形成一个或多个芳香性或饱和环状C5-C6单元或二环C10单元,而且所述C1-C50烷基链被0-15个氧原子和/或0-3个羰基中断和/或被0-5个羟基取代,
而且每个相邻的R1-R4和/或R7-R10可相互连接形成六元芳香碳环,或者是连接A、B或W的一个键,
R5和R6相互独立地是如上述定义的基团-E1或者是C1-C4磺基烷基链,
其中:
R11为氢、氟、氯、溴、碘原子或者是硝基或者为-NE1E2、
-OE1或-E1基团,其中E1和E2如上所述,
R12是氢原子或者如上所述的E1基团,
b为0、2、或3,
其中:
R13和R14相互独立地是氢、饱和或不饱和的、直链或支
链的C1-C10烷基链,该烷基链可被最多至5个氧原子中断和
/或被最多至5个羟基取代,而且基团R13和R14可相互连接形
p是2或3的整数,
X和Y相互独立地是O、S、-CH=CH-或CH(CH3)2,
R19和R20相互独立地是基团-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NE1E2、-OE1、-OSO3H、-SO3H、-E1,其中E1和E2如上所述,其条件是,E1和E2不同时为氢原子,
R21和R22相互独立地是如上所述的基团-E1,C1-C4磺基烷基链,
或者R19、R20、R21、R22、E1或E2为连接上述A、B或W的一个键。
通式Ⅰ之化合物进一步特别优选是,其中F是通式Ⅵ的花青染料:其中:
p、X、Y、R21和R22如上所述,
R23是-OE3、-COOE3、-CONHE3、-CONH(CH2)1-6-NHE3、-CONH(CH2)1-6-OE3、-CONH(CH2)1-6-COOE3或者-CONH(CH2)1-6-CONHE3,其中E3是具有至少一个-SO3H基团的单糖、寡糖或多糖。
通式Ⅰ之其它特别优选的化合物是,其中F是通式Ⅶ的Oxonol染料:其中:
p、R19和R20如上所述,
R24和R25相互独立地是被羟基、羧基、硫酸、磺酸、烷基或烷氧基或羧酸酯基单取代-三取代的苯环。
通式Ⅰ之本发明化合物是,其中A例如是抗体、抗体片段、特异性肽和蛋白质、受体、酶、酶底物、核苷酸、核糖核酸、脱氧核糖核酸、脂蛋白、碳水化合物、单糖、二糖或三糖、线性或分枝寡糖或多糖或它们的衍生物或者是右旋糖。
优选的肽是β-淀粉样蛋白1-40、1-42和1-43及其部分结构和衍生物。特别优选的是用氨基酸半胱氨酸改性的β-淀粉样蛋白和β-淀粉样蛋白的部分结构,其中,通过马来酰亚胺结构在半胱氨酸的巯基上连接F。
单体氨基糖例如是葡糖胺、半乳糖胺、甘露糖胺、古洛糖胺、果糖胺、3-氨基-3-脱氧-核糖、Kanosamin、海藻糖胺、碳霉糖、德糖胺、Rhodosamine、6-氨基-6-脱氧-葡萄糖、Neosamin、Paromose。
氨基糖-羧酸例如是葡糖胺酸、葡糖胺醛酸、胞壁酸、海藻糖胺、软骨生及衍生物、壳三糖。
通式Ⅰ的化合物优选是,其中在氨基糖的氨基和染料的羧基之间形成酰胺基由此连接F。
通式Ⅰ的其它化合物优选是,其中A为单糖、二糖、三糖、和寡糖,其配糖中羟基转化为氨基,然后通过形成酰胺基实现与染料F之羧基的连接。
单糖-寡糖是丙醛糖和丙酮糖至庚醛糖和庚酮糖、辛酮糖和壬酮糖、脱水氨基糖、赛克拉特(Cyclite)、氨基糖和二氨基糖、脱氧糖、氨基脱氧糖、单羧酸糖、氨基糖-羧酸、氨基赛克拉特、单糖至寡糖的含磷衍生物。
合适的多糖是岩藻依聚糖、阿糖基半乳聚糖、软骨素及其硫酸酯、皮肤素、肝素、类肝素、乙酰肝素、透明质酸、角质素、聚半乳糖醛酸、聚葡萄糖醛酸、聚甘露糖醛酸、胰岛素、聚乳糖、聚乳糖胺、聚肌苷酸、聚蔗糖、支链淀粉酶、糖原、黑曲霉多糖、出芽短梗霉聚糖、Asparagosin、海葱糖、Sitosin、半乳卡洛糖、淡黄青霉糖、半乳聚糖、甘露聚糖、Guaran、葡甘露聚糖、半乳葡甘露聚糖、磷酸甘露聚糖、岩藻聚糖、果胶、环糊精、以及这些高分子化合物通过化学和/或酶法制得的衍生物、分解产物和裂解产物。
特别优选的单糖、寡糖和多糖是经硫酸化或磷酸化的结构。
经硫酸化的结构例如是葡糖胺-3-硫酸酯、葡糖胺-6-硫酸酯、以及例如根据Jaurand,G.等人,Carbohydrate Research 1994,255:295-301:Bocker,T.等人,Carbohydrate Research,1992,230:245-256的硫酸化法,用合适的试剂对上述单糖、二糖、三糖至寡糖及多糖进行硫酸化而得到的结构。
本发明之选择性结合β-淀粉样蛋白斑的染料B是重氮染料,其共价键地与所述信号分子结合。合适的重氮染料例如是刚果红、柯胺G、Evans兰、Chicago天兰6B、Direct Red染料、Direct Yellow染料、Ponceau染料、活性黑5、和Calcion。
通式Ⅰ之化合物优选是,其中B是通式Ⅷ重氮染料:其中:
R15和R16相互独立地是被一个或多个羟基、羧基、氨基、磺酸、烷氧羰基、烷基氨基、二烷基氨基、烷氧基或者芳基磺酰基取代的苯基或萘基,所述烷基中有最多6个碳原子,而所述芳基磺酰基中的芳基最多有9个碳原子;或者是染料F;
R17和R18相互独立地是羟基、羧基、磺酸、带有最多至6个碳原子的烷基、烷氧基。
通式Ⅰ之本发明化合物进一步优选是,其中W是-OSO3H或者-SO3H,最多带有60个碳原子的直链、支链、环状或多环烷基、烯基、多烯基、炔基、芳基、烷芳基或芳烷基,它们被最多5个羟基、最多3个羧酸基和至少一个-OSO3H或-SO3H基团取代。
通式Ⅰ的化合物优选是,其中W是经硫酸化的结构,其通过硫酸化相应的羟基化合物来制备。
合适的例如是氨基醇,其中氨基和染料中的羧基通过形成酰胺基而实现连接,然后将羟基硫酸化。氨基醇的例子是2-氨基-1-乙醇、3-氨基-1-丙醇、4-氨基-1-丁醇、5-氨基-1-戊醇、6-氨基-1-己醇、3-氨基-1,2-丙二醇、2-氨基1,3-丙二醇、3-氨基-1,2,4-丁三醇、羟基苯胺、4-氨基间苯二酚。
通式Ⅰ之本发明化合物的制备是按照本领域技术人员已知的方法通过聚亚甲基染料基体的修饰来进行,所述染料基体包含可偶联官能度(如羧基、氨基、羟基)。
因此,在得到起始化合物结构的同时,这些基团可按照本领域已知的方式,通过与相应的取代基反应来进行修饰。
聚亚甲基染料基体的合成根据文献已知的方法来进行,例如:F.M.Hamerin The Cyanine Dyes and Related Compounds,John Wiley and Sons,New Yor,1964;Cytometry,10(1989),3-10;11(1990)418-430;12(1990)723-30;Bioconjuate Chem.4(1993)105-11;Anal.Biochem.217(1994)197-204;Tetrahedron 45(1989)4845-66;EP-0591 820 A1;J.Org.Chem.60(1995)2361-95。
本发明之染料-生物分子加成物(通式Ⅰ中l不等于零)是根据文献已知的方法通过使染料与生物分子A反应来制备的。染料因此必须有可偶联的活性基团,或者染料必须通过原位或者事先产生这些基团来进行活化。对于生物分子中的氨基和巯基,活性基团例如是N-羟基琥珀酰亚胺基酯、N-羟基-琥珀酰亚胺基酯-3-硫酸、异硫氰酸酯、异氰酸酯、马来酰亚胺基、卤代乙酰基、乙烯磺酸基。偶联优选在含水介质中进行。在此情况下加料可根据化学计量和反应时间来调节。文献:Synth.Commun.23(1993)3078-94;DE-OS 3912046;CancerImmunol.Immunother.41(1995)257-263;Cancer Research 54(1994)2643-49。
本发明的又一个目的是通式Ⅰ之本发明化合物通过NIR-辐射体内诊断神经变性疾病的应用。
本发明的再一个目的是通式Ⅰ之本发明化合物在体外诊断中的应用。
为此,得到组织样品或活组织样品,并检查它们的β-淀粉样蛋白折叠结构的含量。
出乎意料地,本发明的染料选择性地结合在待检查的样品上,并借助于在近红外光谱范围内的特异性发射的荧光而得到利用。
本发明的再一个目的是提供用于体内诊断的诊断剂,其包括通式Ⅰ的化合物以及常规助剂和载体及稀释剂。
根据本发明,在用于体内诊断时,优选通过鞘内、腰髓内或静脉内向组织给药一种或多种所述物质,然后辐射出近红外范围内的光。同时/单独记录未被吸收并散射出的光和/或由染料发射并散射出的荧光辐射。该方法优选是,其中组织大面积地辐射,并用CCD照相机拍摄局部释放的荧光辐射,或者用光导体扫描待成象的组织区域,然后用计算机将得到的信号转化为合成图象。此外,光谱和/或相选择性地以及稳定和/或分辨时间地利用荧光。
与放射诊断法相比,本发明化合物的优点例如在于,由于使用了更为稳定的染料,可以在施用后的较长时间范围内通过激发染料产生荧光信号,并进行检测。这满足了诊断所需要的较长时间,因为例如由于半衰期产生的限制就不存在了。
利用本发明就可以不必使用侵入性诊断方法,而直接在体内检测淀粉样蛋白斑。
以下实施例进一步说明本发明。实施例1制备N-(2,3-二硫酸根)丙基-1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸酰胺,三钠盐1)1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸-N-羟基琥珀酰基酯,三钠盐
在0.5g(0.7mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸和0.1g(0.9mmol)N-羟基琥珀酰亚胺在30ml无水DMF的溶液中,于0℃下在氩气中滴加0.15g(0.75mmol)N,N′-二环己基碳化二亚胺。在室温下搅拌72小时。然后在高真空下于40℃蒸发溶剂至约为5ml,并将残留物在200ml乙醚中搅拌。倾析乙醚后,将产生的沉淀物重新用5ml二甲基甲酰胺溶解,并重复所述过程。所得的沉淀物在高真空下干燥,并于-20℃下在氩气中保存。
产率:0.55g(97%),深兰色粉末2)N-(2,3-二羟基)丙基-1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸酰胺,三钠盐
0.5g(0.61mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸-N-羟基琥珀酰基酯溶解在20ml二甲基甲酰胺中,加入0.15g(0.92mmoL)2-氨基甲基-5,5-二甲基-1,3-二氧戊环-盐酸盐和0.1g(1.1mmol)三乙基胺在20ml二甲基甲酰胺中的溶液,在室温下搅拌24小时。如上所述进行处理。粗产物在室温下于30ml水/甲醇/乙酸(3∶1∶2)中搅拌18小时,该溶液直接进行色谱纯制(Europrep,60-30C18,60A,20-45μ,洗脱剂:水/甲醇)。
产率:0.25 g(52%),兰色冻干物3)N-(2,3-二硫酸根)丙基-1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸酰胺,三钠盐
在室温下使0.25g(0.32mmol)N-(2,3-二羟基)丙基-1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸酰胺与0.22g(1.6mmol)三氧化硫-三甲基胺复合物在15ml二甲基甲酰胺中一起搅拌48小时。蒸发浓缩反应混合物,用乙醚搅拌,然后色谱纯化所沉淀的固体物质(Europrep,60-30C18,60A,20-45μ,洗脱剂:0.5%NaCl溶液/甲醇)。
产率:0.20g(64%),兰色冻干物λmax,吸收(H2O)=746nmλmax,荧光(H2O)=780nm实施例2二-1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸-α-D-葡糖胺-3″-硫酸酯,二钠盐(2)
在0.5g(0.7mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸和0.1g(1.0mmol)三乙胺在20ml无水DMF的溶液中加入0.23g(0.7mmol)苯并三唑-1-基-N,N,N′,N′-四甲基尿-四氟硼酸(TBTU)。在室温下搅拌30分钟后,滴加0.36g(1.4mmol)α-D-葡糖胺-3-硫酸酯和0.15g(1.5mmol)三乙基胺在25ml无水二甲基甲酰胺中的溶液。在室温下继续搅拌3小时。在高真空下于40℃蒸发溶剂,并将残留物在乙醚中搅拌。过滤所形成的固体物质,在RP硅胶柱(Europrep,60-30 C18,60A,20-45μ,洗脱梯度:100% 0.5%NaCl溶液->90%0.5%NaCl溶液/10%甲醇->90%水/10%甲醇->50%甲醇)上进行色谱纯制,然后冷冻干燥。
λmax,吸收(H2O)=745nm
λmax,荧光(H2O)=779nm实施例3二-1,1′-(4-磺基丁基)indotricarbo花青-5,5′-二羧酸-二-α-D-葡糖胺-二-3″-硫酸酯,三钠盐(3)
类似于实施例2进行制备和纯制,不同之处在于,用0.5g(0.66mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5,5′-二羧酸,0.2g(2.0mmol)三乙胺在25ml二甲基甲酰胺中,添加0.43g(1.32mmol)TBTU以及0.69g(2.64mmol)α-D-葡糖胺-3-硫酸酯和0.3g(3mmol)三乙基胺在30ml二甲基甲酰胺中。
λmax,吸收(H2O)=754nm
λmax,荧光(H2O)=790nm实施例4N-软骨生-二-1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸酰胺,钠盐(4)
类似于实施例2进行制备,不同之处在于,用0.5g(0.7mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5-二羧酸,并使用0.43g(1.2mmol)软骨生。反应时间为5小时。用HPLC进行纯制(柱:250×20mm,Nucleosil 100C18,7mm,洗脱剂:50mM磷酸盐缓冲液pH4/甲醇,在60分钟内甲醇由5%上升至95%),随后在RP-硅胶上脱盐,并进行冷冻干燥。
产率:0.35g(48%),兰色冻干物
λmax,吸收(H2O)=746nm
λmax,荧光(H2O)=779nm实施例5麦芽三糖-Indotricarbo花青加成物1)制备1-氨基-1-脱氧-麦芽三糖
0.2g麦芽三糖在5ml饱和碳酸氢铵中于30℃搅拌7天。除去过量的碳酸氢铵,将溶液多次冻干至恒重。2)与1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸偶联
0.1g(0.14mmol)1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸和15mg三乙基胺在5ml二甲基甲酰胺中的溶液加入0.05g(0.15mmol)O-(苯并三唑-1-基)-N,N,N′,N′-四甲基尿-四氟硼酸(TBTU),然后在室温下搅拌30分钟。继续加入0.14g(0.28mmol)1-氨基-1-脱氧-麦芽三糖,并在室温下再搅拌5小时。在40℃下真空除去二甲基甲酰胺后,用乙醚搅拌残留物,过滤,并用色谱纯制(Europrep,60-30 C18,60A,20-45μ,洗脱剂:水/甲醇)。冻干后产率50%。
λmax,吸收(H2O)-748nm
λmax,荧光(H2O)=779nm实施例6肝素-Indotricarbo花青-加成物
根据类似于Nagasawa K.和Inoue Y.的方法(Carbohydrate Chemistry,Vol.Ⅲ,1980,291-294)对0.25g肝素(低分子量,M约为6000g/mol,Sigma制造)进行部分去-N-硫酸化(25℃下3小时:产率0.20g)。
将0.10g部分去-N-硫酸化的低分子量肝素溶解在40ml磷酸盐缓冲液(0.1M磷酸二氢钠/磷酸氢二钠,pH8.3)中,加入0.12g(0.15mmol)1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸-N-羟基琥珀酰基酯钠盐(见实施例1)在4ml二甲基甲酰胺中的溶液,在室温下搅拌2小时。用蒸馏水(Centriprep 3000,Amicon制造)进行超过滤来纯制,冷冻干燥,在真空下于50℃干燥5小时。硫含量(用ICP-AES测量)S(%)肝素 11.55S(%)部分去-N-硫酸化的 10.02S(%)用染料标记后的 10.89λmax,吸收(H2O)=750nmλmax,荧光(H2O)=782nm实施例7Indotricarbo花青-Cys-β-淀粉样蛋白-加成物1)制备N-[3-(3-马来酰亚胺基苄氧基)氨基丙基]-二-1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸酰胺,钠盐
根据已知的文献方法通过与3-氨基丙基-叔丁基氨基甲酸酯的反应,用三氟乙酸进行酸性裂解使氨基游离,然后与3-马来酰亚胺基苯甲酰氯反应,由此使1,1′-二(4-磺基丁基)indotricarbo花青-5-羧酸转化为标题化合物。2a)用Cys-β-淀粉样蛋白(1-40)标记
用氩气饱和,使所有溶剂除去氧。
10mg经冻干的Cys-β-淀粉样蛋白(1-40)溶解在1ml磷酸盐缓冲液pH 7.8/DMF(2∶1混合物)中,然后添加10mg的N-[3-(3-马来酰亚胺基苄氧基)氨基丙基]-二-1,1′-(4-磺基丁基)indotricarbo花青-5-羧酸酰胺钠盐。室温下搅拌3小时,用5ml水稀释,然后冻干溶液。
用HPLC(柱:Merck Select B,5μ;洗脱剂:水+0.05%三氟乙酸,乙腈)纯制,得到4mg产物。λmax,吸收(H2O)=747nmλmax,荧光(H2O)=780nm2b)用Cys-β-淀粉样蛋白(12-20)标记
类似2a)进行反应。使5mgCys-β-淀粉样蛋白(12-20)与10mg染料反应,然后在室温下搅拌2.5小时。用HPLC纯制后得到6mg产物。实施例8通过荧光检测测定染料结构与βA4-肽结合的结合实验1)制备涂敷βA4-肽的膜并温育结合βA4的染料结构
本结合实验在涂敷βA4-肽的硝基纤维素膜(纤维素硝酸酯膜过滤器CN;0.4μm,Schleicher&Schuell制造)上进行。膜的涂敷在一个Dot-Blot室(Stratagene制造)中进行。该膜和吸墨纸(GB002,Schleicher&Schuell制造)用水弄湿,然后在TBST缓冲液(20mM Tris/HCl pH7.6;127mM NaCl;0.1%Tween 20;0.01%NaN3)中平衡。
将在0.2ml TBST缓冲液中的10、5和2.5μg肽涂敷在从βA4-肽的水溶液(2mg/ml)中取出的膜上。温育15分钟后,通过膜吸入肽溶液,用0.2ml TBST缓冲液冲洗,从Dot-Blot室中取出膜,然后在37℃干燥30分钟。
在与染料温育前,温育经干燥的膜,同时与TBST-Block缓冲液(TBST,同上;5%乳色粉末)轻轻摇动2小时,然后用TBST缓冲液洗涤5分钟。与染料的温育通过轻轻摇动在0.005-0.05%染料之TBST溶液中的膜来进行。然后用TBTS缓冲液洗涤5次,在室温下干燥膜,并封接住。2)荧光检测评估
将激光诱导的荧光照片转化为实际的荧光成象系统。用波长为740nm的单色激光通过光导系统辐射的输出耦合和纤维素膜的均匀照明来进行激发。反射的激发光被缝隙式过滤器分流,而激光诱导的荧光在740nm以上,用CCD(电荷偶联装置)照相机对其进行摄像,并将数据存储为黑白图象。
在图1和2中,显示了膜荧光照片的例子。图1:
在与二-1,1′-(4-磺基丁基)indotricarbo花青钠盐(0.005%溶液)温育后纤维素膜的荧光照片
激发波长740nm;检测>780nm
1:2.5μg β-淀粉样蛋白(1-42)
2:5μg β-淀粉样蛋白(1-42)
3:10μg β-淀粉样蛋白(1-42)
4:在纤维素膜上具有类似结合性质的对照肽图2:
在与4-[5-[3-羧基-3-羟基-1-(4-磺基苯基)-1H-吡唑-4-基]-2,4-戊二烯基]-4,5-二氢-5-氧-1-(4-磺基丁基)-1H-吡唑-3-羧酸二钾盐(0.005%溶液)温育后纤维素膜的荧光照片
激发波长650nm;检测>680nm
5:2.5μg β-淀粉样蛋白(1-42)
6:5μg β-淀粉样蛋白(1-42)
7:10μg β-淀粉样蛋白(1-42)
8:在纤维素膜上具有类似结合性质的对照肽
Claims (13)
1、通式Ⅰ的化合物及其药物学上可接受的盐:
Fm(-Al)(-Bn)(-Wo) (Ⅰ)其中:
F是染料信号分子,其至少在600-1200nm的范围内具有一个最大吸收,
A是结合β-淀粉样蛋白斑的生物分子,
B是结合β-淀粉样蛋白斑的染料,
W是结合β-淀粉样蛋白斑的、亲水性的低分子结构单元,
m是1或2的整数,或者当n和o是零时,其为3-20的整数,
l和n相互独立地是0、1、或2,
o是0、1、2、3、或4的整数,
其条件是,l、n和o的和大于等于1。
2、如权利要求1所述的化合物,其特征在于,在通式Ⅰ中F是花青、Squarilium、Croconium、部花青、或Oxonol染料。
R1-R4以及R7-R10相互独立地是氟、氯、溴、碘原子或者是硝基或-COOE1、-CONE1E2、-NHCOE1、-NHCONHE1、-NEuE2、-OE1、-OSO3E1、-SO3E1、SO2NHE1、-E1,其中E1和E2相互独立地是氢,饱和或不饱和的、直链或支链的C1-C50烷基链,该链或部分该链可选择性地形成一个或多个芳香性或饱和环状C5-C6单元或二环C10单元,而且所述C1-C50烷基链被0-15个氧原子和/或0-3个羰基中断和/或被0-5个羟基取代,
而且每个相邻的R1-R4和/或R7-R10可相互连接形成六元芳香碳环,或者是连接A、B或W的-个键,
R5和R6相互独立地是如上述定义的基团-E1或者是C1-C4磺基烷基链,
其中:
R11为氢、氟、氯、溴、碘原子或者是硝基或者为-NE1E2、
-OE1或-E1基团,其中E1和E2如上所述,
R12是氢原子或者如上所述的E1基团,
b为0、2、或3,
其中:
R13和R14相互独立地是氢、饱和或不饱和的、直链或支
链的C1-C10烷基链,该烷基链可被最多至5个氧原子中断和
/或被最多至5个羟基取代,而且基团R13和R14可相互连接形
成5或6元环。
7、如前述权利要求之一所述的化合物,其特征在于,在通式Ⅰ中A是抗体、抗体片段、特异性肽和蛋白质、受体、酶、酶底物、核苷酸、核糖核酸、脱氧核糖核酸、脂蛋白、碳水化合物、单糖、二糖或三糖、线性或分枝寡糖或多糖或它们的衍生物或者是右旋糖。
9、如前述权利要求之一所述的化合物,其特征在于,在通式Ⅰ中W是-OSO3H或者-SO3H,最多带有60个碳原子的直链、支链、环状或多环烷基、烯基、多烯基、炔基、芳基、烷芳基或芳烷基,它们被最多5个羟基、最多3个羧酸基和至少一个-OSO3H或-SO3H基团取代。
10、如前述权利要求之一所述的化合物,其特征在于,F与A、B和/或W相互独立地通过酯、醚、仲胺或叔胺基、酰胺基或以下基团而连接在一起:
11、如权利要求1所述的化合物在通过NIR辐射体内诊断神经变性疾病中的应用。
12、如权利要求1所述的化合物在通过NIR辐射体外诊断神经变性组织中的应用。
13、通过NIR辐射体内诊断神经变性疾病的光学诊断剂,其特征在于,其包含至少一种如权利要求1所述的化合物以及常规助剂和载体及稀释剂。
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-
1996
- 1996-11-19 DE DE19649971A patent/DE19649971A1/de not_active Withdrawn
-
1997
- 1997-10-29 CN CN97199895A patent/CN1237911A/zh active Pending
- 1997-10-29 EP EP97948710A patent/EP0942756A2/de not_active Withdrawn
- 1997-10-29 CA CA002272320A patent/CA2272320A1/en not_active Abandoned
- 1997-10-29 JP JP52305998A patent/JP2001506591A/ja not_active Withdrawn
- 1997-10-29 WO PCT/DE1997/002559 patent/WO1998022146A2/de active Application Filing
- 1997-10-29 AU AU72985/98A patent/AU7298598A/en not_active Abandoned
- 1997-10-29 US US09/308,177 patent/US6329531B1/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108135903A (zh) * | 2015-09-09 | 2018-06-08 | 目标实验室有限责任公司 | 靶向psma的nir染料及其应用 |
US11484607B2 (en) | 2015-09-09 | 2022-11-01 | On Target Laboratories, LLC | PSMA-targeted NIR dyes and their uses |
Also Published As
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WO1998022146A2 (de) | 1998-05-28 |
AU7298598A (en) | 1998-06-10 |
WO1998022146A3 (de) | 1998-10-15 |
DE19649971A1 (de) | 1998-05-28 |
CA2272320A1 (en) | 1998-05-28 |
JP2001506591A (ja) | 2001-05-22 |
EP0942756A2 (de) | 1999-09-22 |
US6329531B1 (en) | 2001-12-11 |
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