CN1174511A - 利用近红外线辐射进行体内诊断的方法 - Google Patents
利用近红外线辐射进行体内诊断的方法 Download PDFInfo
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- CN1174511A CN1174511A CN95196624A CN95196624A CN1174511A CN 1174511 A CN1174511 A CN 1174511A CN 95196624 A CN95196624 A CN 95196624A CN 95196624 A CN95196624 A CN 95196624A CN 1174511 A CN1174511 A CN 1174511A
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Abstract
本发明涉及一种基于近红外辐射(NIR辐射)的体内诊断方法。该方法使用了分别具有特定的光物理学和药物化学特性的水溶性染料及其生物分子加成物作为NIR范围内的荧光法和透照法诊断的对照介质。本发明还涉及新染料以及包括该染料的药物。
Description
本发明涉及一种基于近红外辐射(NIR辐射)的体内诊断方法,该方法使用了分别具有特定的光物理学和药物化学特性的水溶性染料及其生物分子加成物作为NIR范围内的荧光法和透照法诊断的对照介质。本发明还涉及新染料以及包括该染料的药物。
对疾病的诊断能力很大程度上依赖于从不易够着的深层组织中所获的有关结构及其变化的信息。除了扪诊,暴露或者穿刺这些组织外,也可以通过使用复杂的照相法诸如X-射线,磁共振X线断层术,或者超声诊断来获取这些信息。
由于生物组织对650-1000nm的长波长光表现出了较高的穿透性,因此诊断者可以使用一种完全不同的组织影像学方法。在近红外范围内的光能穿透几厘米的组织的事实可用于透照成像。到目前为止,此项技术便于鼻窦和上颌窦炎症的诊断以及组织表层的体液或血液的聚积的检测(Beuthan J.,Muller G.;红外透照,医学技术,1(1992)13-17)。
至今,人类对检测胸部肿瘤的种种努力的效果仍不理想(Navarro,G.A.;Profio,A.E.;胸部透视对照;医学生理,150(1988)181-187;Aspegren,K.,在筛查和临床实践中检测乳房癌的光扫描与乳房造影术,癌65(1990)1671-77),但在未来却可能因为最近技术的进步而得到更好的结果(Klingenbeck J.;利用NIR光的激光乳房造影,Gynakol-Geburtsh-Randsch.33增刊.1(1993)299-300);Benaron D.A.;技术进步带来的光学影像的再生,影像诊断(Diagnostic Imaging)(1994)69-76)。
除了检测非吸收射线外,在近红外光处理后发出的荧光射线也可以提供组织的具体信息。这种所谓的自身荧光用于区别动脉粥样硬化组织和正常组织(Henry,P.D.等,激光诱发的人体动脉的自身荧光,循环研究(Circ.Res.)63(1988)1053-59)。
应用近红外线的主要问题是其异常宽的光散射从而尽管具有不同的光物理学特征但也只能提供一个清晰轮廓的目标的相当模糊的影像。该问题随着离表面的距离越远而增加并且也可认为是透照法和荧光射线检测的主要限制因子。
积聚在病变组织(尤其是肿瘤)中以及表现出特殊的吸收和激发行为的合适的荧光染料可有助于扩大健康组织和病变组织的区别。由于吸收散射光而引起的变化,或者由激发射线而诱发的荧光能用于检测并且提供实际组织的具体信息。
使用染料在人体内诊断的实例是标记血以便测定分布区域,血流,或者代谢和排泄功能,以及观察眼睛的透明结构(眼科)的测光法。此种应用的优选染料是吲哚花青绿和荧光素(Googe J.M.等人,手术中荧光素的血管造影术(Intraoperative Fluorescein Angiography),眼科学,100,(1993),1167-70)。
吲哚花青绿(心绿)用于测定肝功能,心脏输出和心搏量以及通过组织的血流和外周血流(医学会(I.Med)24(1993)10-27);此外,它们也用作肿瘤检测的对比介质。吲哚花青绿结合于白蛋白达到100%并且在肝脏中动员。在含水环境中,荧光量子效率低。其LD50(0.84mmol/kg)则足够大;剧烈的过敏反应可能发生。吲哚花青绿在溶解时不稳定并且由于将发生沉淀,所以不能在含盐介质中使用。
欲用于光促治疗(PDT)的光敏剂(包括血卟啉衍生物,原卟啉II,苯卟啉,四苯基卟啉,氯气,酞菁)已用于定位和观察肿瘤而到现在(Bonnett R.;用于肿瘤光促治疗的新光敏剂,SPIE Vol.2078(1994))。上述化合物的一种共同缺点是它们在波长650一1200nm的范围内吸收只是中等。PDT所需的光毒性对单纯的诊断目的来说是干扰,其它关于这些主题的描述是:US-PS 4945239;WO 84/04665,WO 90/10219,DE-OS4136769,DE-PS 2910760。
US-PS 4945239描述了大量的使用透照法检测乳房癌的设备并提到已知的荧光素,荧光胺,以及核黄素作为改进对照的吸收染料。这些染料有一共同缺点是它们的吸收是在400-600nm内的可见光范围内,而该光波对组织的光穿透能力很低。
DE-OS 4136769描述一种用于检测那些富集了荧光物质的组织区域内的荧光的仪器。这些物质是细菌叶绿素及其衍生物,以及萘花青。这些结构在700-800nm的范围内表现出吸收并且吸收系数达到70000l·mol-1·cm-1。除了它们的荧光特征外,这里所述的化合物还可通过辐射而产生单线态氧,从而具有细胞毒效后(用于光促治疗的光敏剂)。该光敏活性对单纯的非活性的诊断剂来说是相当不希望有的。
而且,细菌叶绿素化合物的合成是昂贵的并且在当天然产物作为原始材料时需要大量的工作;然而,该萘花青通常只表现出很低的光稳定性。已知的这些类型的化合物几乎不溶于水,并且合成均匀的亲水衍生物的代价高。
WO 84/04665描述了一种体内荧光检测肿瘤的方法,该方法使用了如下光敏剂:血卟啉及其衍生物(Hp和HpD),尿卟啉和粪卟啉以及原卟啉和许多内消旋取代卟啉,以及诸如核黄素,荧光素,吖啶橙黄,硫酸黄连素和四环素的染料。该物质不能满足上述的光物理学和药物化学要求。
Folli等人,癌研究(Cancer Research)54,2643-2649(1994),描述了一种和花青染料相关的用于检测皮下植入的肿瘤的单克隆抗体。然而,深层病变的检测则需要许多改进的染料。鉴于预料的副作用,较高的染料剂量使得抗体用作载体不适当。
花青染料和相关的聚甲炔染料也用作照像层。这些染料无需任何发光特性。已合成出具有发光(荧光)特性的花青染料用于荧光显微检测和流式细胞检测并和诸如包括碘乙酰的化合物的生物分子相偶合作为蛋白质的巯基的特殊标记试剂。(Waggoner,A.S.等人;用于巯基的花青染料标记试剂,血细胞计数(Cytometry),10,(1989),3-10)。用这处方法标记并分离蛋白。参考文献还有:血细胞计数12(1990)723-30;分析通讯25(1992)415-28;生物共轭化学(Bioconjugate Chem.)4(1993)105-11。
Waggoner,A.S.的DE-OS3912046描述了一种用花青和诸如部花青等类似染料以及包括至少一个磺酸根或者磺酸基的苯乙酰基标记生物分子的方法。该描述涉及在含水条件下的一步和两步标记方法,其共价反应发生在染料和蛋白质或者其它生物分子上的氨基,羟基,醛基或者巯基间。
DE-OS3828360叙述了用荧光素和吲哚花青绿(眼科用)标记抗肿瘤抗体,特别是黑色素瘤和结肠癌的抗体的方法。吲哚花青绿和生物分子结合的键并非共价键(染料-抗体结合物,混合物)。
就目前的技术水准来说,已知的使用NIR射线的体内诊断方法都有一些缺点从而限制了它们在医学诊断方面的广泛应用。
直接用可见光或者NIR射线只能限于机体的表层,这是由于入射光的广泛散射所致。
加入染料可以改进对比度和溶解性,然而却带来了一系列其它问题。该染料应该满足那些一般用于诊断的药品的要求。由于这些物质大多以较高剂量使用并且诊断时间也较长,所以它们应是低毒性的。此外,用于诊断的合适染料应该较好地溶于水并且至少在诊断期内具有足够的化学和光物理学稳定性。在全身代谢方面的稳定性也是必要的。
至今,还没有找到以NIR射线进行体内诊断的染料和合适的方法。
因此,本发明的一个目的就是提供一种能克服以前技术的缺点的体内诊断方法。
这个问题可以按照本发明所提供的方法,即使用NIR射线的体内诊断方法而解决,其中使用通式I的化合物及其生理可接受的盐:
Bl-(F-Wn)m(I)
其中:
l代表从0到6的数字,n代表从0到10的数字,而m则代表从1到100的数字。
B是分子量达到30000的生物检测单元,它可以结合于特定的细胞群或选择性结合于受体,或者聚积于组织或肿瘤,或者普遍地分布于血液中,或者作为非选择地结合的大分子;
F代表一种在650到1200nm范围内具有最大吸收的染料;
W代表可改进水溶性的亲水基团,并且按照分子式I的化合物在l=0时其正辛醇-水的分布系数不大于2.0。
对按照本发明的方法特别适合的通式I的化合物是例如那些其中的B是一种氨基酸,一种肽,CDR(互补决定区),一种抗原,一种半抗原,一种酶底物,一种酶辅助因子,生物素,类胡萝卜素,激素,神经激素,神经递质,生长因子,淋巴因子,植物凝血素,毒素,碳水化合物,低聚糖,高聚糖,右旋糖酐,寡核苷酸或者结合受体的药物。
此外,对按照本发明的方法特别适合的通式I的化合物是例如那些其中的F代表通式IIa的花青染料
其中的r代表数字0,1或者2,并且当r=2时,分别重复出现的片段L6和L7可以是相同或不同的,
L1到L7是相同或者不同的,每个独立代表片段CH或者CR,其中的R是卤素,羟基,羧基,乙酸基,氨基,硝基,氰酸或者磺酸基或者是含有达6个碳原子的烷基,链烯基,羟烷基,羧烷基,烷氧基,烷氧羰基,磺烷基,烷氨基,二烷氨基或者卤代烷基残基,含有碳原子达到9个的芳基,烷芳基,羟芳基,羧基芳基,磺基芳基,芳氨基,二芳基氨基,硝基芳基或者卤代芳基残基,或者其中的R代表一个与另一R残基结合并和分散的L1到L7残基共同形成4到6元环的键,或者其中的R代表分别在两个通过-CO-片段相联的不同位置的键,
R3到R12是相同的或者不同的,各自独立代表氢原子,上述的B或者W残基,或者含有达6个碳原子的烷基或链烯基残基或者含有达9个碳原子的芳基或者芳烷基残基,该烷基,链烯基,芳基或者芳烷基残基选择性地带有一个附加的上述W残基,或者与可以是饱和的,非饱和的或者芳族的并且还可以选择性地带有上述附加的R残基的5或6元环一起在适当考虑散开的碳原子下而稠合到每对相邻的残基R3到R10,
X和Y是相同的或者不同的,各自独立代表O,S,Se或Te或者-C(CH3)2-,-CH=CH-或者-CR13R14-片段,其中R13和R14独立地代表氢原子,上述的B或W残基,或者含有碳原子达到6个的烷基或链烯基或者含有碳原子达到9个的芳基或者芳基烷基残基,烷基,链烯基,芳基或者芳烷基残基可选择性地带有上述附加的残基W,
F也可以代表通式为IIb的方形(squarain)染料其中:s和t独立地代表数字0或者1,但s和t不能同时代表数字1,并且R3到R12,X和Y如上述,F还可以代表通式为IIc的苯乙烯基染料其中的r,L1到L6,R3到R11和X如上述,或者F代表通式为IId的部花青染料其中:r,L1到L6,R3到R8,R11和X如上述,而G则代表氧或者硫原子。特别适合于本发明方法的通式I的化合物是,例如其中:W是羧基或磺酸基或含有达12个碳原子的羧烷基或烷氧羰基或烷氧氧代烷基,
W还可以代表通式III的残基
-(CH2)a-O-Z or (-CH2-CH2-O)a-Z (III)
其中:
a代表数字0到6,
Z包括氢原子或者是含有3到6个碳原子的烷基,并且该烷基含有2到n-1个羟基,这里的n是C原子的数目,或者是带有2到4个附加羟基并含有6到10个碳原子的芳基或者芳烷基残基,或者是带有1到3个附加羧基并含有1到6个碳原子的烷基残基,或者是带有1到3个附加羧基并含有6到9个碳原子的芳基残基或者含有6到15个碳原子的芳烷基残基或者硝芳基或者硝基芳烷基残基或者含有2到4个碳原子并带有1到3个附加羧基的磺烷基残基,
或者W代表通式IIIa或IIIb的残基
或者W代表通式IIIc的残基
-(CH2)o-(CO)p-NR1-(CH2)s-(NH-CO)q-R2 (IIIc)
其中:
o和s独立代表数字0,1,2,3,4,5,或者6,
p和q独立代表0或者1,
R1和R2独立地代表如上述的除通式IIIa和IIIb取代基外的残基Z,或者独立地代表通式IIId或者IIIe的残基
此时的p和q=1
或者代表如上述的通式IIIc的残基。
用于按照本发明的方法的化合物的特征在于它们在波长650到1200nm的范围内有吸收和发荧光,其吸收系数约为100000l·mol-1cm-1或者更高,并且其中的荧光是必需的,其荧光量子效率高于5%,该化合物在体内和体外都有足够的水溶性,耐受性和稳定性,并且还有光稳定性。它们能在尽可能短的时间内尽可能彻底地排出。按照本发明使用的化合物易于合成并且可从市场购得的原始材料经过少许反应步骤而廉价地获得。
当在体内诊断中使用按照本发明的方法时,将通式I的一种或几种物质对组织给药,例如通过静脉注射,然后用从可见到近红外的650到1200nm的范围光照射它们。分开或同时记录没有吸收的射线和荧光射线,或者延时后的互相衬托。从所获的资料中可以组成合成的影像。
可以使用多种方法记录荧光影像。优选的是那些广泛照射组织并用具有局部分辨力的计算机控制(CCD)摄像机观察荧光信息的方法,或者是那些用集中于光导纤维中的光线扫描要造影的组织扇面并用计算机将所获得的信号转换成影像的方法。该光波以窄带并且波长接近最大吸收的幅度发射或者以本发明的化合物荧光激发波长发射。如上所述记录那些没有吸收的射线,并处理所获得的信号。
照射角度和观察角度可以针对每一个病例的解剖和最佳对比的要求而进行选择。该方法的灵敏度可以通过除去给药染料前后的影像而得以改进。求得相关于染料的变化的时间曲线可以揭示有助于诊断的辅助信息。
所用的测定方法是本领域的熟练技术人员所熟悉的。这些专家也知道在按照本发明所使用的通式I的染料的给定的吸收或荧光波长下应该设置什么设备参数以便获得最佳记录和处理条件。
由于该染料体系F的可变结构从而使得按照本发明的方法所使用的通式I的化合物占据了宽广范围的激发和发射波长。有可能获得这样的产品,即其激发波长和特定的激发源如二极管激光器相对应,并因此适应所给的测量系统或者设备元件。
所描述的技术甚至可以定位在深层组织中或者不透明体液中的体积小到只有几mm3的小目标。由于光散射及其所致的有限的分辨率,所以还难以测定此类目标的确切形状和体积,但是解决一些重要的诊断问题时无需这些信息。
令人惊异的是,用CCD摄相机应用花青染料后得到的小鼠(瑞士裸鼠)的荧光透视影像的荧光强度比用了相近剂量的卟啉的小鼠大1000倍。
所描绘的使用本发明的化合物的方法尤其适合于观察那些没有病理改变,全身性疾病,肿瘤,血管,动脉粥样硬化,血小斑,灌泡和扩散的组织。
按照本发明所使用的化合物可以用不同的方式应用于组织。尤其优选地是静脉给药该染料。
剂量可以根据使用目的的不同而完全不同。要达到的目标是一个在诊断区域内的组织中的染料的可检测浓度,而组织或体液中1-100μg/ml的浓度多半是足够的。此浓度可通过直接注射进入小体腔或小血管或淋巴管而达到,并且正常情况下是使用由0.1到10ml的载体液所携带的0.1-100mg的各种染料。在这种情况下,优选地为1到10mg的染料。染色血管或检测特定组织或结构多半需要静脉注射较高剂量(不少于100mg)。剂量的上限只是因每个物质和制剂的耐受性而定。
因此,本发明涉及B1-(F-Wn)m型化合物的使用,其中的F代表来自聚甲炔染料,尤其是花青染料的一种染料。也可使用部花青,苯乙烯基,氧鎓醇类和方形鎓(squarilium)染料。W则是一个对整个分子的水溶性必不可少的结构成份。特别优选地,该化合物的l代表数字0,而其正辛醇/水分散系数小于2(正辛醇/含有0.9%的NaCl的0.01M Tris缓冲液,调pH至7.4,两相彼此饱和)。
生物检测单元可以是例如氨基酸,肽,CDR(互补决定区),抗原,半肮原,酶底物,酶辅助因子,生物素,类胡萝卜素,激素,神经激素,神经递质,生长因子,淋巴因子,植物凝血素,毒素,碳水化合物,低聚糖,高聚糖,右旋糖酐,抗核酸酶的寡核苷酸或者是结合受体的药物。
上述组中的化合物包括例如催产素,后叶加压素,血管紧张素,黑素细胞-刺激激素,tyrotropin释放激素,促性腺激素-释放激素,睾丸素,雌二醇,黄体酮,皮质醇,醛固醇,维生素D,胃泌素,分泌素,促生长激素,胰岛素,胰高血糖素,降钙素,生长激素释放激素,促乳素,脑磷脂,多巴胺,去甲肾肾腺素,5-羟色胺,肾上腺素,白细胞介素,血管生成素,胸腺生成素,促红细胞生成素,纤维蛋白原,血管生成素,3-甲氨基异茨烷,雷尼替丁,甲氰咪胍,lovastatine,异丙基肾肾腺素衍生物或者转铁蛋白。
这些物质便于通过某些机理针对生物检测单元而积聚在机体的特定部位。这些机理包括结合于胞外结构,通过各种生物转运系统而积累,识别细胞表面或者识别胞内成份。
按照本发明所用的其它化合物,B是一种非选择性结合的大分子,例如多熔素,聚乙二醇,甲氧基聚乙二醇,聚乙烯醇,右旋糖酐,羧基右旋糖酐或者是共价结合于F的阶式聚合物类结构。
按照本发明所用的通式I的化合物中所含的带有羟基的烷基,芳基或者芳烷基残基是诸如2-羟基-乙基-,2-羟基-丙基-,3-羟基-丙基-,4-羟基-丁基-,2,3-二羟基-丙基-,1,3-二羟基丙-2-基-,三(羟甲基)-甲基-,1,3,4-三羟丁-2-基-葡糖基-,4-(1,2-二羟乙基)苯基-或者2,4-,2,5-,3,5-或者3,4-二羟苯基的残基。
含有1到3个羧基的烷基,芳基或者芳烷基可以是例如羧甲基,羧乙基,羧丙基,羧丁基,1,2-二羧乙基,1,3-二羧基丙基,3,5-二羧基苯基,3,4-二羧基苯基,2,4-二羧基苯基或者4-(1,2-二羧基乙基)-苯基残基。
磺烷基优选地为2-磺乙基-,3-磺丙基和4-磺丁基残基。
尤其优选地是那些其中W占据R4或R8,R6或R10和R11或R12位置,并且在R3/R5或者R7/R9位置重复出现的化合物。
按照本发明所用的染料的吸收光谱范围在650nm到1200nm之间。其吸收系数约为100000l·mol-1cm-1并且对一个染料分子则会更高。所有用作荧光造影的染料的荧光量子效率都高于5%。
其中的R30代表氢原子,羟基,羧基,含有1到4碳原子的烷氧残基或氯原子,b是一个整数(2或者3),R31代表氢原子或是含有1到4个碳原子的烷基。
X和Y独立地代表-O-,-S-,-CH=CH-或者-C(CH2R32)(CH2R23)-片段。
R20到R29,R32和R33独立地代表氢原子,羟基,羧基,磺酸残基或者是含有达10个碳原子的羧基烷基,烷氧羰基或者烷氧氧代烷基或者是含有达4个碳原子的磺基烷基,
或者是一种非选择性结合的大分子或者是一种如通式VI的残基
-(O)v-(CH2)o-CO-NR34-(CH2)s-(NH-CO)q-R35
此时,其中的X和Y是O,S,-CH=CH-或者-C(CH3)2-,在R20到R29残基中至少有一个对应于一种非选择性结合的大分子或是一种如通式VI的化合物,
其中:
o和s为0或独立地代表1到6间的整数,
q和v独立地代表0或者1,
R34代表氢原子或者甲基,
R35代表含有3到6个碳原子并包括2到n-1个羟基的烷基,而n是碳原子的数量,或者是含有1到6个碳原子并带有1到3个附加羧基的烷基,含有6到9个碳原子的芳基或者含有7到15个碳原子的芳烷基,或者是如通式IIId或者IIIe的残基
此时q是1,
或者是一种非选择性结合的大分子,
R20和R21,R21和R22,R22和R23,R24和R25,R25和R26,R26和R27,与分散的碳原子一起形成一个5或6元芳香或饱和的稠和环。
在按照本发明的如通式V的化合物中,含有羟基或者羧基的烷基,芳基或者芳烷基且有上述的优选组成。
特别优选的花青染料如下:
5-〔2-〔(1,2-二羧乙基)氨基〕-2-氧代乙基〕-2-〔7-〔5-〔2-(1,2-二羧乙基)氨基〕-2-氧代乙基〕-1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐,氢钾盐,
2-〔7-〔5-〔2-〔(11-羧基-2-氧代-1,4,7,10-四吖-4,7,10-三(羧甲基)-1-十一基〕氨基〕-2-氧代乙基〕-1,3-二氢-3,3-二甲基-1-乙基-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐,
2-〔7-〔1,2-二氢-3,3-二甲基-5-〔2-〔(甲氧聚氧乙烯)-氨基〕-2-氧代乙基〕-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-5-〔2-〔(甲氧聚氧乙烯)氨基〕-2-氧代乙基〕-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
2-〔7-〔1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-5-(甲氧聚氧乙烯)氨羰基-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
3-(3-羧丙基)-2-〔7-〔3-(3-羧丙基)-1,3-二氢-3-甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3-甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
2-〔(3-(3-羧丙基)-1,3-二氢-3-甲基-1-(4-磺丁基)2H-吲哚-2-亚基〕甲基〕2-羟基-4-氧代-2-环丁烯-1-亚基〕甲基〕-1,1-二甲基-3-乙基-1H-苯并吲哚鎓,钠盐,
2-〔7-〔1,3-二氢-5-〔2-〔(2,3-二羟丙基)氨基〕-2-氧代乙基〕-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-5-〔2-〔(2,3-二羟丙基)氨基〕-2-氧代乙基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐。
本发明的化合物以及按照本发明所用的化合物的另一个重要特征是其正辛醇/水分散系数小于2.0(分散系数正辛醇/0.01M TRIS缓冲液,其中含0.9%的NaCl,调pH到7.4,两相彼此饱和)表示的亲水性。该化合物没有任何作为诊断试剂无需的特殊光敏性或者光毒性。它们的耐受性和排泄良好。
本发明的化合物的亲水行为使其区别于那些已用于体内诊断的染料。特别是花青染料,由于聚集,其荧光量子效率值在含水环境中大大降低,并可和在非极性溶剂中测得的值可比;增加其在水中的溶解度以及亲水基团所要求的空间则可以抑制聚集物和胶团的形成。
一组优选的化合物几乎不表现蛋白亲和性,其药动学行为和诸如胰岛素或者蔗糖等相近。
令人惊异的是这些化合物虽然只是简单分子结构,但却在机体的特定结构如肿瘤中表现出了特征性的充分积聚。当该染料均匀地通过机体时,相对于周围组织,其在肿瘤区域的排除滞后。
该物质的耐受性很好。尤其优选的是那些单染料分子的LD50值大于0.5mmol/kg体重的物质。
本发明的化合物以及按照本发明所用的化合物的特征在于其在体内和体外的强大的稳定性以及光稳定性。当将该水溶液置于日光室内,2天后,98%的特别优选的化合物没有变化,而在12天后,则有70%的没有变化。
本发明的化合物以及按照本发明所用的化合物的光物理和药动学特性也不同于那些只是作为花青染料而批准应用于人体的化合物:靛青绿(心绿)。
本发明的另一目的是通式I的化合物,其中B的l值不小于1,优选地为1或者2。
可以合成出当吸收光在650到1200nm波长范围内具有很高的消光系数并且以很高的效率发射荧光的花青染料。本发明的花青染料以及按照本发明所使用的花青染料的合成主要参照文献的已知方法,例如,F.M.Hamer的花青染料及其相关化合物,John Wilev和Sons,New York,1964;血细胞计数,10(1989)3-10;11(1990)418-430;12(1990)723-30;生物共轭化学,4(1993)105-11,分析生物化学,217(1994)197-204;四面体45(1989)4845-66,欧洲专利申请0 591 820 A1。
按照本发明所使用的通式I的染料-生物分子加合物是通过按照上述方法制备的已知化合物F-Wn和生物检测单元B反应而制备的。
因此,该化合物F-Wn应含有至少一个,优选地为正好一个能和生物检测单元上的氨基,羟基,醛基或者巯基进行共价反应的基团。这些基团从文献已知并且详细描述于诸如DE-OS 39 12 046。
特别优选的是那些能和氨基官能团起反应并形成硫脲,脲以及酰胺桥的异硫氰酸酯,异氰酸酯和羟基琥珀酰亚胺酯或者羟基磺基琥珀酰亚胺酯基团,以及那些能和巯基基团起反应并形成硫醚桥的卤代乙酰基和琥珀酰亚胺基团。
此外,带有醇官能团的羧基基团可以用合适的活化剂(如DCC)形成酯键或醚结构,而醛官能团能和肼结合形成亚胺结构。
将前述的反应基团加入到本发明的染料或者按照本发明使用的通式I的染料或者其合成的前体中,或者存在的官能团转变成反应基团。这些反应基团可以通过所谓的连接物结构(如烷基链,芳烷基结构)而直接和染料系统相联。
在pH值为7.4到10,该F-Wn化合物优选地和DMF或含水环境中或者DMF/水混合物中的生物检测单元B起反应。染料和生物分子的摩尔份数(装填比)是用吸收分光计来测定的。那些没有结合的组份则通过色谱法或过滤除去。
那些具有合适官能团的大分子则用同样的方式和染料偶合。
这些物质可以具有十分不同的特性。它们的分子量可以从几百到100000以上。这些物质可以是中性的或者带电荷的。酸性染料盐以及生理可接受的碱,诸如钠,甲基谷氨酸,赖氨酸,或者那些包括阳离子的锂,钙,镁,钆的盐。
如此所得的染料-生物分子加成物能极好地满足上述光物理学,毒理学,化学以及经济学的要求。
本发明的另一个目的是类似于通式I化合物的使用的通式V的花青染料利用NIR射线进行体内诊断的应用。
本发明还有一个目的就是包括通式V或者I的化合物的诊断试剂。
这些试剂可以按照本领域的熟练技术人员所熟悉的方法通过选择性地加入常规的辅助剂,稀释剂及其类似物而制备。这包括生理耐受的电解质,缓冲液,洗涤剂以及那些调节渗透性的物质和那些诸如环化糊精的改进稳定性和溶解性的物质。在制备过程中和尤其在使用前的制剂的无菌状态是通过制药业中常规的步骤来确保的。
本发明还将通过下述实施例而得以解释。
实施例
实施例1
制备5-[2-[(1,2-二羧乙基)氨基]-2-氧代乙基]-2-[7-[5-[2-(1,2-二羧乙基)氨基]-2-氧代乙基]-1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓内盐,氢钾盐。
二-N-羟基琥珀酰亚胺酯是按照已知方法(血细胞计数11(1990)418-430)由5-羧甲基-2-[7-[5-羧甲基-1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐,氢钾盐制备的。
将0.16g(1.22mmol)的天冬氨酸的1ml DMF溶液加入0.5g(0.51mmol)二琥珀酰亚胺酯的5ml DMF溶液中。将反应混合物于室温搅拌48小时。加入醚而沉淀出产物,在RP-18(LiChroprep,15-25μ,H2O∶MeOH 99∶1到1∶1)上纯化并冻干。在50℃/0.01毫巴的条件下干燥24小时后可得到0.27g(51%)产品。
分析:计算值:C 54.43 H 5.54 N 5.40 O 24.68 S 6.18 K 3.77测定值:C 54.04 H 5.81 N 5.22 S 6.13 K 3.85
实施例2
制备2-[7-[5-[2-[(11-羧基-2-氧代-1,4,7,10-四吖-4,7,10-三(羧甲基)-1-十一基]氨基]-2-氧代乙基]-1,3-二氢-3,3-二甲基-1-乙基-2H-吲哚-2-亚基]-1,3,5-庚三烯基-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐。
将溶于1ml甲醇中的43mg(0.65mmol)的85%的水合肼于-10℃缓慢滴加入0.5g(0.73mmol)2-[7-[5-(羧甲基)-1,3-二氢-3,3-二甲基-1-乙基-2H-吲哚-2-亚基]-1,3,5-庚三烯基-3,3-二乙基-1-(4-磺丁基)-3H-吲哚鎓-N-琥珀酰亚胺酯,内盐的5ml甲醇溶液中(血细胞计数11(1990)418-430)并在此温度下搅拌2小时。将该反应混合液真空蒸发至约3ml,再和1ml异丙醇混和并且在-20℃过夜。吸取沉淀的结晶并用油泵干燥。该产物是0.27g(61%)三羰花青碳酸酰肼。
在搅拌条件下,将0.27g(0.45mmol)酰肼加入0.21g(0.51mmol)的二亚乙基三胺五乙酸单乙酯单酐的20ml DMF和0.2ml三乙基胺溶液中。将该混合液于室温中连续搅拌48小时。过滤后,于0.2毫巴蒸发溶剂,残渣和CH2Cl2混合,过滤,真空干燥。将所得产物在室温中和5ml的3M NaoH水溶液搅拌4小时。然后,用半浓缩的HCl调pH值至2.0。加入1ml的异丙醇。将该混合物置于4℃ 18小时后,吸取沉淀晶体并在60℃高真空干燥24小时。
产量:0.23g(52%)暗红颗粒。
分析:计算值:C 59.32 H 6.60 N 9.88 O 20.96 S 3.23测定值:C 54.15 H 6.70 N 9.50 S 3.19
实施例3
制备2-[7-[1,3-二氢-3,3-二甲基-5-[2-[(甲氧基聚氧乙烯)-氨基]-2-氧代乙基]-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-5-[2-[(甲氧聚氧乙烯)氨基]-2-氧代乙基]-1-(4-磺丁基)-3H-吲哚鎓,钠盐
将实施例1中的溶于1ml DMF中的0.08mmol N,N-二琥珀酰亚胺酯加入800mg甲氧基聚氧乙烯胺(约0.16mmol;平均摩尔质量约5000)的10ml CH2Cl2溶液中并在室温中持续搅拌24小时。将加入醚后而沉淀的固体产物过滤并用色谱纯化(Sephadex G50柱,H2O作为洗脱液),冻干(P2O5)后得到产率约为58%的绿蓝色粉末。
平均摩尔质量计算值:10771,测定值:10820
实施例4
2-[7-[1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-5-(甲氧基聚氧乙烯)氨基羰基]-1(4-磺丁基)-3H-吲哚鎓,钠盐
将0.41g(0.5mmol)2-[7-[ 1,3-二氢-3,3-二甲基-1-(4-磺丁基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-5-羧基-4(4-磺丁基)-3H-吲哚鎓-N-琥珀酰亚胺酯,钠盐在氩气中和2.3g甲氧基聚氧乙烯胺(0.46mmol;平均摩尔质量:5000)的70ml CH2Cl2溶液于室温下搅拌18小时。真空除去一半溶剂并按实施例3所述分离产品。产物是2.1g的绿蓝色粉末。
平均摩尔质量计算值:5701,测定值:5795
实施例5
制备3-(3-羧丙基)-2-[7-[3-(3-羧丙基)-1,3-二氢-3-甲基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3-甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐。
将6.5g(50mmol)苯肼盐酸盐和8.7g(55mmol)5-甲基-6-氧代庚酸在50ml浓乙酸中于室温搅拌1小时,然后在120℃5小时。蒸发浓缩后,残渣和20ml水混合,将沉淀的结晶过滤并用油泵干燥。
将所得9.6g(83%)褐色晶体产物悬浮于60ml二氯苯中,并在加入11.6g(85mmol)1,4-丁烷磺内酯后,加热至150℃8小时。混合物冷却至室温后,加入200ml丙酮,过滤沉淀。悬浮于醚中,搅拌18小时后再过滤,用油泵干燥。所得产物是10.7g(70%)3-(3-羧丙基)-2,3-二甲基-1-(4-磺丁基)-3H-假吲哚,它通过色谱(RP-18,Li Chroprep,15-25μ,MeOH∶H2O作为洗脱液)纯化。
该吲哚三羰花青染料是通过加热溶于100ml乙酸酐中的5.0g(13.6mmol)假吲哚和1.9g(6.8mmol)戊烯二醛双苯胺盐酸盐至120℃30分钟,并加入25ml浓乙酸和2.3g(27.6mmol)无水乙酸钠而制备的。在所得沉淀中加入500ml醚,通过色谱(1.0克,RP-18,LiChroprep,15-25μ,MeOH∶H2O作为洗脱液)纯化并最终冻干。产物是2.5g(45%)终产品。
分析:计算值:C 60.13 H 6.28 N 3.42 O 19.54 S 7.83 Na 2.81测定值:C 59.90 H 6.34 N 3.39 S 7.72 Na 2.78
实施例6
制备2-[[3-[[3-(3-羧丙基)-1,3-二氢-1-(4-磺丁基)2H-吲哚-2-亚基]甲基]2-羟基-4-氧代-2-环丁烯-1-亚基]甲基]-1,1-二甲基-3-乙基-1H-苯并吲哚鎓,内盐
将3.65g(10.0mmol)3-乙基-1,1,2-三甲基-1H-碘化苯吲哚鎓加入1.36g(8.0mmol)方形酸二乙基酯和1.6ml三乙基胺的12ml乙醇溶液中,加热至70℃。在80℃搅拌10分钟后,将该混合物冷却至0℃。过滤所沉淀的红色结晶,用醚洗涤,并真空干燥。在硅胶(CH2Cl2∶AcOH9∶1到7∶3)色谱柱上纯化得到1.33g(46%)的2-乙氧基-1-[(3-乙基-1,1-二甲基-1H-苯吲哚-2-亚基)-甲基]-环丁烯-3,4-二酮。
将该物质悬浮于15ml的煮沸的乙醇中并和15ml的40%NaOH搅拌混和。将所得溶液于80℃搅拌5分钟并在其冷却至室温后和5ml的2NHCl混合。过滤蒸发后的沉淀1-[(3-乙基-1,1-二甲基-1H-苯吲哚-2-亚基)-甲基]-2-羟基环丙烯-3,4-二酮(1.30g),干燥并不经纯化用于下步合成。
该方形染料是通过所得的1.30g(3.9mmol)方形酸衍生物和1.43g(3.9mmol)3-(3-羧丙基)-2,3-二甲基-1-(4-磺丁基)-3H-假吲哚反应而制成。将得组份在80ml甲苯和80ml 1-丁醇中于水分离器上加热18小时,然后真空除去溶剂。残渣与醚混合,于室温搅拌16小时后,过滤所形成的晶体,并用色谱(RP-18,LiChroprep,15-25μ,MeOH∶H2O作为洗脱液)纯化,产量:0.95g(36%)。
分析:计算值:C 68.60 H 6.20 N 4.10 O16.40 S 4.70测定值:C 68.25 H 6.35 N 4.04 S 4.59
实施例7
制备2-[7-[1,3-二氢-5-[2-[(2,3-二羟基丙基)氨基]-2-氧代乙基]-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-5-[2-[(2,3-二羟丙基)氨基]-2-氧代乙基]-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐
将2.0g(6.4mmol)2,3,3-三甲基-3H-吲哚-5-基乙酸琥珀酰亚胺酯的50ml CH2Cl2溶液和0.84g(6.4mmol)4-氨甲基-2,2-二甲基-1,3-二氧戊环混合。室温搅拌5小时后,加入100ml水于混合物中并用CH2Cl2抽提;蒸发掉有机相。色谱(硅胶CH2Cl2∶MeOH 98∶2)纯化后,获得1.86g酰胺,并将其在20ml二氯苯和1.36g(10.0mmol)的1,4-丁烷磺内酯中于室温和100℃搅拌12小时。和50ml丙酮一起搅拌该混合物后,过滤所形成的颗粒,并用色谱(RP-18,LiChroprep,15-25μ,MeOH∶H2O作为洗脱液)纯化。产物是0.85g(相当于原始化合物的28%)5-[2-[(2,2-二甲基-1,3-二噁-4-环戊基)甲基]氨基-2-氧代乙基]-2,3,3-三甲基-1-(4-磺丁基)-3H-假吲哚。
制备染料的反应类似于实施例4。将该物质加热至120℃10分钟。将该粗产品于室温在5ml MeOH中加入100mg甲苯-对-磺酸后搅拌16小时,除去不溶成份。然后,将加入3ml异丙醇后的滤液置于-20℃。将沉淀粉末通过色谱(RP-18,LiChroprep,15-25μ,MeOH∶H2O作为洗脱剂)纯化,冻干并在50℃/0.01毫巴的条件下干燥24小时。产量:0.32g(37%)
分析:计算值:C 56.70 H 6.45 N 5.88 O 20.14 S 6.73 K 4.10测定值:C 56.39 H 6.88 N 5.67 S 6.58 K 3.93
实施例8
将2-[7-[1,3-二氢-3,3-二甲基-5-(甲氧羰基)-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-5-(甲氧羰基)-1-(4-磺丁基)-3H-吲哚鎓,钠盐按3.8μmol/kg体重的剂量对麻醉的带瘤鼠(瑞士裸鼠,右后腿肿瘤LS 174T)静脉给药。
在给予该物质之前以及之后的不同时间,用荧光成像器(PhysikalischTechnische Bundesanstalt,Berlin Charlottenburg)进行激光诱导荧光成像。通过光导纤维系统分离射线使用在740nm的单色激光激发射线。低于740nm的激发射线用滤光器除去。高于740nm的激光诱发的荧光用CCD(电荷耦合设备)摄相机记录,并将资料用黑白图像保存下来。
如图1所示的连续图像清楚地表明了应用了该物质后,荧光强度的普遍增长(A,B)。30秒后可以观察到强度的均匀分布,而在肝脏和肺部区域以及肿瘤中,强度值有增长(B)。随着时间的推移(至1小时)(C,D,E),该物质越来越扩散至动物全身。18小时后,可以观察到和身体其余部分相比,肿瘤处(右后腿)有明显的荧光强度增长。
图1表明在静脉给药3.8mmol/kg体重的2-[7-[1,3-二氢-3,3-二甲基-5-(甲氧羰基)-1-(4-磺丁基)-2H-吲哚-2-亚基]-1,3,5-庚三烯基]-3,3-二甲基-5-(甲氧羰基)-1-(4-磺丁基)-3H-吲哚鎓,钠盐后的不同时间的小鼠(瑞士裸鼠)的荧光图像(黑白)。
A-E:右侧图像,F:后部图像
A:给药前,
B:30秒,
C:1分钟,
D:10分钟,
E:给药后1小时
F:给药后18小时。
Claims (8)
1.基于NIR射线的体内诊断方法,使用通式I的化合物及其生理可接受的盐:
B1-(F-Wn)m(I)
其中:
l代表从0到6的数字,n代表从0到10的数字,而m则代表从1到100的数字。
B是分子量达到30000的生物检测单元,它可以结合于特定的细胞群或选择性结合于受体,或者聚积于组织或肿瘤,或者普遍地分布于血液中,或者作为非选择地结合的大分子;
F代表一种在650到1200nm范围内具有最大吸收的染料;
W代表可改进水溶性的亲水基团,并且按照分子式I的化合物在l=0时其正辛醇-水的分布系数不大于2.0。
2.按权利要求1的方法,其特征是,通式I中的B包含一种氨基酸,一种肽,CDR(互补决定区),一种抗原,一种半抗原,一种酶底物,一种酶辅助因子,生物素,类胡萝卜素,激素,神经激素,神经递质,生长因子,淋巴因子,植物凝血素,毒素,碳水化合物,低聚糖,高聚糖,右旋糖酐,寡核苷酸或者结合受体的药物。
其中的r代表数字0,1或者2,并且当r=2时,分别重复出现的片段L6和L7可以是相同或不同的,
L1到L7是相同或者不同的,每个独立代表片段CH或者CR,其中的R是卤素,羟基,羧基,乙酸基,氨基,硝基,氰酸或者磺酸基或者是含有达6个碳原子的烷基,链烯基,羟烷基,羧烷基,烷氧基,烷氧羰基,磺烷基,烷氨基,二烷氨基或者卤代烷基残基,含有碳原子达到9个的芳基,烷芳基,羟芳基,羧基芳基,磺基芳基,芳氨基,二芳基氨基,硝基芳基或者卤代芳基残基,或者其中的R代表一个与另一R残基结合并和分散的L1到L7残基共同形成4到6元环的键,或者其中的R代表分别在两个通过-CO-片段相联的不同位置的键,
R3到R12是相同的或者不同的,各自独立代表氢原子,上述的B或者W残基,或者含有达6个碳原子的烷基或链烯基残基或者含有达9个碳原子的芳基或者芳烷基残基,该烷基,链烯基,芳基或者芳烷基残基选择性地带有一个附加的上述W残基,或者与可以是饱和的,非饱和的或者芳族的并且还可以选择性地带有上述附加的R残基的5或6元环一起在适当考虑散开的碳原子下而稠合到每对相邻的残基R3到R10,
X和Y是相同的或者不同的,各自独立代表O,S,Se或Te或者-C(CH3)2-;-CH=CH-或者-CR13R14-片段,其中R13和R14独立地代表氢原子,上述的B或W残基,或者含有碳原子达到6个的烷基或链烯基或者含有碳原子达到9个的芳基或者芳基烷基残基,烷基,链烯基,芳基或者芳烷基残基可选择性地带有上述附加的残基W,
F也可以代表通式为IIb的方形染料其中:s和t独立地代表数字0或者1,但s和t不能同时代表数字1,并且R3到R12,X和Y如上述,F还可以代表通式为IIc的苯乙烯基染料其中的r,L1到L6,R3到R11和X如上述,或者F代表通式为IId的部花青染料
其中:
r,L1到L6,R3到R8,R11和X如上述,而G则代表氧或者硫原子。
4.按前述权利要求至少一项的方法,其特征是,通式I中的W是羧基或磺酸基或含有达12个碳原子的羧烷基或烷氧羰基或烷氧氧代烷基,
W还可以代表通式III的残基
-(CH2)a-O-Z or(-CH2-CH2-O)a-Z(III)
其中:
a代表数字0到6,
Z包括氢原子或者是含有3到6个碳原子的烷基,并且该烷基含有2到n-1个羟基,这里的n是C原子的数目,或者是带有2到4个附加羟基并含有6到10个碳原子的芳基或者芳烷基残基,或者是带有1到3个附加羧基并含有1到6个碳原子的烷基残基,或者是带有1到3个附加羧基并含有6到9个碳原子的芳基残基或者含有6到15个碳原子的芳烷基残基或者硝芳基或者硝基芳烷基残基或者含有2到4个碳原子并带有1到3个附加羧基的磺烷基残基,
-(CH2)o-(CO)p-NR1-(CH2)s-(NH-CO)q-R2 (IIIc)
其中:
o和s独立代表数字0,1,2,3,4,5,或者6,
p和q独立代表0或者1,
其中的R30代表氢原子,羟基,羧基,含有1到4碳原子的烷氧残基或氯原子,b是整数2或者3,R31代表氢原子或是含有1到4个碳原子的烷基。
X和Y独立地代表-O-,-S-,-CH=CH-或者-C(CH2R32)(CH2R23)-片段。
R20到R29,R32和R33独立地代表氢原子,羟基,羧基,磺酸残基或者是含有达10个碳原子的羧基烷基,烷氧羰基或者烷氧氧代烷基或者是含有达4个碳原子的磺基烷基,
或者是一种非选择性结合的大分子或者是一种如通式VI的残基
-(O)v-(CH2)o-CO-NR34-(CH2)s-(NH-CO)q-R35
(VI)
此时,其中的X和Y是O,S,-CH=CH-或者-C(CH3)2-,在R20到R29残基中至少有一个对应于一种非选择性结合的大分子或是一种如通式VI的化合物,
其中:
o和s为0或独立地代表1到6间的整数,
q和v独立地代表0或者1,
R34代表氢原子或者甲基,
R35代表含有3到6个碳原子并包括2到n-1个羟基的烷基,而n是碳原子的数量,或者是含有1到6个碳原子并带有1到3个附加羧基的烷基,含有6到9个碳原子的芳基或者含有7到15个碳原子的芳烷基,或者是如通式IIId或者IIIe的残基
此时q是1,
或者是一种非选择性结合的大分子,
R20和R21,R21和R22,R22和R23,R24和R25,R25和R26,R26和R27,与分散的碳原子一起形成一个5或6元芳香或饱和的稠和环。
6.按权利要求5的花青染料,即
5-〔2-〔(1,2-二羧乙基)氨基〕-2-氧代乙基〕-2-〔7-〔5-〔2-(1,2-二羧乙基)氨基〕-2-氧代乙基〕-1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐,氢钾盐,
2-〔7-〔5-〔2-〔(1 1-羧基-2-氧代-1,4,7,10-四吖-4,7,10-三(羧甲基)-1-十一基〕氨基〕-2-氧代乙基〕-1,3-二氢-3,3-二甲基-1-乙基-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,内盐,
2-〔7-〔1,2-二氢-3,3-二甲基-5-〔2-〔(甲氧聚氧乙烯)-氨基〕-2-氧代乙基〕-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-5-〔2-〔(甲氧聚氧乙烯)氨基〕-2-氧代乙基〕-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
2-〔7-〔1,3-二氢-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-3,3-二甲基-5-(甲氧聚氧乙烯)氨羰基-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
3-(3-羧丙基)-2-〔7-〔3-(3-羧丙基)-1,3-二氢-3-甲基-1-(4-磺丁基)-2H 吲哚-2-亚基〕-1,3,5-庚三烯基〕-3-甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐,
2-〔(3-(3-羧丙基)-1,3-二氢-3-甲基-1-(4-磺丁基)2H-吲哚-2-亚基〕甲基〕2-羟基-4-氧代-2-环丁烯-1-亚基〕甲基〕-1,1-二甲基-3-乙基-1H-苯并吲哚鎓,钠盐,
2-〔7-〔1,3-二氢-5-〔2-〔(2,3-二羟丙基)氨基〕-2-氧代乙基〕-3,3-二甲基-1-(4-磺丁基)-2H-吲哚-2-亚基〕-1,3,5-庚三烯基〕-5-〔2-〔(2,3-二羟丙基)氨基〕-2-氧代乙基〕-3,3-二甲基-1-(4-磺丁基)-3H-吲哚鎓,钠盐。
7.按权利要求5或6的花青染料通过NIR射线进行体内诊断的使用。
8.一种体内诊断剂,其特征是其包括至少一种按权利要求5或者6的花青染料以及常规辅助剂,底物,和稀释剂。
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