CN1158133A - 肽衍生的放射性核素螯合剂 - Google Patents
肽衍生的放射性核素螯合剂 Download PDFInfo
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- CN1158133A CN1158133A CN95195127A CN95195127A CN1158133A CN 1158133 A CN1158133 A CN 1158133A CN 95195127 A CN95195127 A CN 95195127A CN 95195127 A CN95195127 A CN 95195127A CN 1158133 A CN1158133 A CN 1158133A
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- compound
- alkyl
- amino
- carboxyl
- hydroxyl
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- 238000012360 testing method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
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Abstract
本发明提供了式(I)放射性核素螯合剂,以用在体内要诊断的显影位点。式(I)中X是直链或支链的、饱和或不饱和C1-4烷基链,此烷基链可任选地插入一个或两个选自N、O和S的杂原子;并且可任选地被至少一个选自卤素、羟基、氨基、羧基、C1-4烷基、芳基和C(O)Z的基团取代;Y是H或X限定的取代基;X和Y可以一起形成一个5-至8-元的饱和或不饱和杂环,该杂环可任选地被至少一个选自卤素、羟基、氨基、羧基、氧化、C1-4烷基、芳基和C(O)Z的基团取代;R1至R4各自独立地选自H、羧基;C1-4烷基;被选自羟基、氨基、巯基、卤素、羧基、C1-4烷氧羰基和氨基羰基的基团取代的C1-4烷基;除脯氨酸的D-或L-氨基酸的α-碳侧链;C(O)Z;R5和R6各自独立地选自H;羧基;氨基;C1-4烷基;被羟基、羧基或氨基取代的C1-4烷基;和C(O)Z;R7选自H和硫保护基;Z选自羟基、C1-4烷氧基和靶向性分子。
Description
发明领域
本发明属于诊断造影领域,涉及用来对以所要诊断的组织为靶的试剂进行放射性标记的化学螯合剂。
发明背景
诊断造影技术中采用造影剂,其选择性地结合或定位于体内位点,帮助分辨所要诊断部位的影象。例如67镓盐具有对肿瘤和被感染组织的亲和性,并且借助于X射线断层扫描照相术能够使医生发现受伤的体内组织。其它造影剂包括金属放射性核素,如99m锝和186/188铼,其已被用来标记靶向分子,诸如位于人体特定部位的蛋白质、肽和抗体。
作为靶向试剂,蛋白质和其它大分子能提供满足诊断准确性要求的组织特异性;但从其物质结构而言,用金属放射性核素标记这些试剂很困难。具体而言,蛋白质和肽靶向试剂存在可与放射性核素结合的多个位点,从而得到不均匀标记的产物。而且,尽管这些蛋白质分子可能很大,但其很少能呈现出一种最适于与高亲和性放射性核素结合的结构构型,即结合有4个或多个供体原子形成5元环的区域,因此,放射性核素通常被结合于较为丰富的低亲和性位点,形成不稳定配合物。
为解决这种低亲和力结合问题,Paik等人(Nucl Med Biol 1985,12:3)提出了一种方法,其中在过量DPTA(二氨亚丙基五乙酸)存在下对抗体进行标记,使低亲和力结合位点隐蔽起来。虽然通过这种方法能避免低亲和力结合问题,但这种情况中实际上放射性核素锝的结合量最终仍是很低的。已有文献报道了具有高半胱氨酸残基比例的蛋白质的直接标记(Dean等;WO 92/13572)。该方法利用了半胱氨酸残基中的巯基作为放射性核素结合的高亲和性位点,并且该方法必须限于应用在那些具有所需巯基结构的靶向性试剂中。
代替靶向性试剂直接标记的一种可行方法是采用间接标记途径,其中使用一螯合剂使靶向性试剂和放射性核素偶联。用作螯合剂的候选物是那些与所选金属放射性核素紧密结合的并且还具有与靶向性分子结合的反应官能团的化合物。为用于标记肽和以蛋白质为基础的靶向性试剂,理想的螯合剂也是以肽为基础的,如此可使用肽合成技术全部合成这些螯合剂-靶向性分子共轭物,为用于诊断造影,理想的螯合剂应具有适于体内应用的性质,诸如血和肾清除性及血管外扩散性。
发明概述
本发明提供了与诊断用金属放射性核素键连的螯合剂,其能与可在体内定位欲诊断位点和欲治疗位点的靶向性试剂偶联。本发明螯合剂为肽类似物,设计其结构存在N3S构型,能键连氧代、二氧代和99m锝及186/188铼的次氮基离子。
其中
X是一直链或支链的、饱和或不饱和的C1-4烷基链,该烷基链可任选地插入一个或两个选自N、O和S的杂原子;并且可任选地被至少一个选自卤素、羟基、氨基、羧基、C1-4烷基、芳基和C(O)Z的基团取代;
Y是H或由X定义的取代基;
X和Y一起形成一个5-至8-元饱和或不饱和杂环,该杂环可任选地被至少一个选自卤素、羟基、氨基、羧基、氧代、C1-4烷基、芳基和C(O)Z的基团取代;
R1至R4各自独立地选自H;羧基;C1-4烷基;被选自羟基、氨基、巯基、卤素、羧基、C1-4烷氧羰基和氨基羰基的一个基团取代的C1-4烷基;除脯氨酸外的D-或L-氨基酸的α-碳侧链;和C(O)Z;
R5和R6各自独立地选自H;羧基;氨基;C1-4烷基;被羟基、羧基或氨基取代的C1-4烷基;和C(O)Z;
R7选自H和硫保护基;及
Z选自羟基、C1-4烷氧基和靶向性分子。
其中
X是一直链或支链、饱和或不饱和C1-4烷基链,该烷基链可任选地插入一个或两个选自N、O和S的杂原子;并且可任选地被至少一个选自卤素、羟基、氨基、羧基、C1-4烷基、芳基和C(O)Z的基团取代;
Y是H或X定义的取代基;
X和Y一起形成5-至8-元饱和或不饱和杂环,该杂环可任选地被至少一个选自卤素、羟基、氨基、羧基、氧代、C1-4烷基、芳基和C(O)Z的基团取代;
R1至R4各自独立地选自H;羧基;C1-4烷基;被一个选自羟基、氨基、巯基、卤素、羧基、C1-4烷氧羰基和氨基羰基的基团取代的C1-4烷基;除脯氨酸外的D-或L-氨基酸的α碳侧链;和C(O)Z;
R5和R6各自独立地选自H;羧基;氨基;C1-4烷基;被羟基、羧基或氨基取代的C1-4烷基;和C(O)Z;
Z选自羟基、C1-4烷氧基和一个靶向性分子;
M是一金属放射性核素或其氧化物或氮化物。
本发明另一方面提供了一种用于造影的共轭物,其中螯合剂所呈形式是与诊断用靶向性分子偶联,并可任选地与配合的金属放射性核素结合。
本发明另一方面提供了一种在所要诊断位点进行造影的方法,其中首先对病人施用作为放射性核素配合物的本发明共轭物,然后用造影方法探测放射性核素所处部位。
附图简述
图1为以99mTc标记的N,N-二甲基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg-OH共轭物的HPLC分析结果。
发明详述
本发明提供了金属放射性核素螯合剂,当其与靶向性分子偶联时,能用来将放射性核素递送至所要治疗或诊断的身体部位。正如上式中所示,该螯合剂为肽化合物,其呈现N3S构型,其中放射性核素被螯合。
这里所用的定义R1-R7、X、Y和Z各种变化的术语含义如下:
“烷基”指直链或支链C1-4链;
“芳基”指芳香环或杂芳香环;
“卤素”指F、Cl和Br;
“硫保护基”指抑制巯基氧化的化学基团,包括那些在金属螯合作用时可被裂解的基团。适合的硫保护基包括已知的烷基、芳基、酰基、链烷酰基、芳酰基、巯酰基和有机硫代基。
在本发明优选实施方案中,螯合剂符合上式,其中
R1至R4各自独立地选自H;羟基取代的C1-4烷基,如羟甲基和1-羟乙基;
R5和R6各自独立地选自H和C1-4烷基,优选均为H;
R7是氢原子或硫保护基,且最优选乙酰氨基甲基;
X是C1-4烷基链,优选甲基或乙基;或被芳基取代的C1-4烷基链,优选形成苄基;
Y是H或X定义的取代基;优选甲基、乙基或苄基,最优选为与X相同;
Z是OH,C1-4烷氧基或一靶向性分子,优选肽靶向性分子。
本发明具体螯合剂包括:
N,N-二甲基Gly-Ser-Cys(Acm)-OH;
N,N-二甲基Gly-Thr-Cys(Acm)-OH;
N,N-二乙基Gly-Ser-Cys(Acm)-OH;
N,N-二苄基Gly-Ser-Cys(Acm)-OH;和
肌氨酸-Ser-Cys(Acm)-OH。
当X和Y代表的取代基与邻接的N原子形成一个杂环时,该环可以是5-至8-元饱和环,例如吡咯烷、哌啶、 1-氮杂环庚烷和1-氮杂环辛烷。由X和Y形成的不饱和环包括吡咯和4H-吡啶,显然环中结合的氮原子必须是三价的且不能与邻位原子形成双键。由X和Y形成的杂环也可包含另外一个或两个选自N、O和S的杂原子。具有另外杂原子的环包括1-咪唑、吡唑、哌嗪、吗啉和硫代吗啉,但不限于这些。由X和Y形成的环也可被一个或多个并优选少于三个基团取代,取代基选自卤素、羟基、羧基、氧代、C1-4烷基和芳基,例如形成4-氧代-1-哌啶、4-氧代-1-吡咯烷和4-羟基-1-哌啶。
为诊断造影目的,本质上螯合剂可呈与金属放射性核素成配合物形式。适宜的放射性核素包括99mTc、64Cu、67Cu、97Ru、105Rh、109Pd、186Re、188Re、198Au、199Au、203Pb、212Pb和212Bi的各种氧化物或氮化物。优选的金属放射性核素为氧化物形式的锝(99mTc)和铼(186,188Re),如ReO3+、ReO2 +、99mTcO2 +,最优选99mTcO3+。根据本发明优选方面,螯合剂与由上式中Z代表的靶向性分子偶联,形成一种结合物,用来向哺乳动物体中目标位点递送螯合的放射性核素。适于与螯合剂偶联的靶向性分子的例子包括但不限于甾族化合物、蛋白质、肽、抗体、核苷酸和糖类。优选靶向性分子包括蛋白质和肽,特别是那些能与具体病理特点的细胞表面受体进行特异结合的肽和蛋白。例如,通过标记与本发明螯合剂偶联的蛋白或其受体结合片段,可对特殊蛋白受体的超表达相关疾病进行造影。最优选的靶向性分子是肽,其能特异地结合于靶位点,且具有三个或多个氨基酸残基。用于某些疾病状况和组织造影的靶向性肽如下所示:针对动脉粥样硬化斑:
YRALVDTLK RALVDTLK
RALVDTLKFVTQAEGAK YAKFRETLEDTRDRMY
AKFRETLEDTRDRMY AALDLNAVANKIADFEL
YAALDLNAVANKIADFEL YRALVDTLKFVTEQAKGA
RALVDTLKFVTEQAKGA YRALVDTEFKVKQEAGAK
RALVDTEFKVKQEAGAK YRALVDTLKFVTQAEGAK针对感染和动脉粥样硬化斑:
VGVAPGVGVAPGVGVAPG 甲酰Nleu.LF.Nleu.YK
VPGVGVPGVGVPGVGVPGVG 甲酰MIFL
甲酰MLFK 甲酰MLFI
甲酰MFIL 甲酰MFLI
甲酰MLIF 甲酰MILF
甲酰TKPR VGVAPG
甲酰MLF YIGSR
CH2CO.YIGSRC针对血栓:
NDGDFEEIPEEYLQ NDGDFEEIPEEY(SO3Na)LQ
GPRG针对血小板:
D-Phe.PRPGGGGNGDFEEIPEEYL RRRRRRRRRGDV
PLYKKIIKKLLES RGD
RGDS针对淀粉样蛋白斑(早老性痴呆):
EKPLQNFTLSFR
为与螯合剂连接,靶向性分子可以包含一个“间隔臂”,以在螯合剂和靶向性分子间形成一个物理间隔。间隔臂可以是一烷基链,其被衍化用于与螯合剂偶联。当靶向性分子是肽时,间隔臂可以是适合的一个或多个氨基酸残基。优选肽靶向性分子含有1至5个氨基酸的间隔臂,这些氨基酸具有化学惰性的α-碳侧链,诸如甘氨酸或β丙氨酸残基。
靶向性分子可以在各种位点包括R1至R6、X、Y和Z及由X和Y形成的环与本发明螯合剂偶联。通过将靶向性分子上反应活性基团与螯合剂上的取代基反应,形成一连接键,完成偶联。例如,具有自由氨基象N-末端或有ε-氨基的Lys基团的肽靶向性分子可以与螯合剂的羧基反应,形成酰胺连接键。或者,肽靶向性分子的C-末端可以与螯合剂的氨基取代基反应。在优选实施方案中,靶向性分子通过一酰胺键如肽键在取代基Z处与式(I)螯合剂偶联。例如,肽靶向性分子的N-末端氨基与Z处的羧基反应。除肽外的靶向性分子,只要其具有适于与螯合剂偶联的基团,均可以以相似的方式与本发明螯合剂偶联。当适宜的基团不存在时,可以将靶向性分子化学衍生出这种基团。当螯合剂或靶向性分子上存在多于1个的反应基团时,应该用合适的封闭剂将除特定的偶联基团外的所有基团封闭,以获得单一共轭物。例如通过形成酯可将自由羧基保护起来,象叔丁酯,其可用TFA去除。用如FMOC封闭基可将自由氨基保护起来,用哌啶可随后将其去除。
在本发明一具体实施方案中,使用一共轭物对体内炎症病灶位点进行造影,其中靶向性分子是包含氨基酸序列Thr-Lys-Pro-Pro-Lys(TKPPR)的趋化性肽。已发现该肽能与白细胞受体很好地结合。通过附加的氨基酸残基(优选甘氨酸)可将靶向性肽与螯合剂间隔开,条件是肽仍保持其定位活性。在一具体实施方案中,通过一Gly残基将肽TKPPR与式(I)螯合剂的取代基Z偶联。
使用各种现有技术可制备以肽为基础的靶向性分子本身或将其与螯合剂一起制备成共轭物。由于其适于固相肽合成,所以采用交替的FMOC保护和去保护是制备短肽的优选方法。生产蛋白质或其长片段时优选用重组DNA技术。在一具体实施方案中,通过固相肽合成方法制备肽-螯合剂共轭物,包括向连接在不溶性(固体)支持物或基质如聚苯乙烯的增长的肽链上逐步增加氨基酸残基。首先将靶向性肽的C-末端残基键连到市售的支持物上,其氨基由N-保护剂如芴甲氧羰基(FMOC)保护。通常,支持物被预先连接上呈被保护形式的C-末端残基。用适宜的去保护试剂如哌啶除去氨基保护基,并用偶联剂如双环碳二亚胺(DCC)连接下一个氨基酸残基(呈N-被保护形式)。肽键形成时,从支持物上洗去反应试剂。一旦合成靶向性肽链,则要向N末端加上螯合剂的第一个残基即S-乙酰氨基甲基保护的半胱氨酸。螯合剂的最后残基是衍生的氨基酸残基,其形成了式(X)(Y)N-C(R1)(R2)-CO-,其中X、Y、R1和R2的定义如前所述。最后一个残基,例如二甲基甘氨酸、二乙基甘氨酸、二苄基甘氨酸或肌氨酸,均可市购或合成。用适宜的试剂如三氟乙酸(TFA)从载体上解离下该完整的共轭物。
显然,根据本发明,所有取代基R1至R4均为天然存在或衍生的氨基酸,包括D-氨基酸的侧链,其可市购且适于固相合成技术。对于购买不到的衍生氨基酸残基,根据现有有机化学技术合成这些氨基酸并在上述固相肽合成的适宜期间插入这些氨基酸,从而可使其掺人本发明螯合剂中。与此类似,当取代基R5和R6不是H时,在肽合成中使用衍生半胱氨酸残基。例如,当R5和R6均为甲基时,掺入市售的青霉胺残基。
通过将X和Y的各种取代基作为固相合成中的最后残基,如式(X)(Y)N-C(R1)(R2)-C(O)-OH所示的衍生的氨基酸,可将其掺入本发明螯合剂中,其中X、Y、R1和R2的含义同前。根据现有有机化学方法和技术可以合成具有N-末端氨基取代基X和Y的氨基酸。例如,当X和Y均为二苄基取代基时,可通过在适当的溶剂如二氯甲烷中将市售试剂溴乙酸和二苄胺反应,然后加热,合成出相应的二苄基甘氨酸残基。在反应中可采用其它胺代替二苄胺,如二异丙胺,得到相应的二异丙基甘氨酸。与此类似,用哌啶和吗啉这种环胺代替二苄胺,可得到相应的哌啶基甘氨酸和吗啉基甘氨酸残基。
在本发明最优选的实施方案中,在固相载体上制备肽-螯合剂共轭物,其具有式(I)结构,其中靶向性分子是序列为Gly-Thr-Lys-Pro-Pro-Arg-OH的肽;R1、R2、R3、R5和R6是H;R4是羟甲基或1-羟乙基,R7是乙酰氨基甲基。
通过各种已知方法可在螯合剂中掺入所选择的放射性核素。例如可使用下述常规方法。首先将螯合剂溶解于乙醇水溶液如乙醇-水1∶1中形成螯合剂溶液。用例如N2排气,除去O2,然后加入氢氧化钠除去巯基保护基,将溶液再次除净氧气,并水浴加热使巯基保护基水解,然后用有机酸如乙酸将溶液中和(pH6.0-6.5)。在标记步骤中,向螯合剂溶液中加入高锝酸钠和足以还原锝的氯化亚锡。将溶液混合,置于室温下反应然后水浴加热。在另一种方法中,可用调至pH8的螯合剂溶液进行标记。在这种较高pH值时,可用含锝的溶液代替高锝酸盐,锝配合有不稳定配基,适于与所需螯合剂进行配基交换反应。适宜的配基包括酒石酸盐、柠檬酸盐和七葡糖酸盐。若螯合溶液另被调节至更高pH如pH12-13,用于标记步骤,则可用连二亚硫酸钠作为还原剂代替氯化亚锡。本发明螯合剂在用放射性核素标记之前可与靶向性分子偶联,此方法即指“双功能螯合”法。另一种途径是“预先标记配基”法,其中先以放射性核素标记螯合剂,再将螯合剂与靶向性分子偶联。
可通过色谱法,例如使用先以乙醇活化然后再用稀HCl活化的C-18Sep Pak柱,可将被标记的螯合剂从污染物99mTcO4和胶态99mTcO2中分离出来。用稀盐酸洗脱分离出99mTcO4,用乙醇-盐水1∶1洗脱带出螯合剂,而胶态99mTcO2存留在柱中。
当本发明螯合剂与靶向性分子偶联并用诊断用金属标记时,可通过诊断造影领域常规技术将其用于检测病理状况。可对哺乳动物施用以放射性核素金属如锝标记的螯合剂-靶向性分子结合物,淋巴内、腹膜内且优选静脉内给予药用溶液中如生理盐水或血浆介质中的药。被标记结合物的给药量取决于所选靶向性分子的毒性曲线和金属的毒性曲线,通常每70kg病人给药范围在0.01至100且优选10至50mCi。通过标准闪烁照相技术在给药后适当的时间体内追踪金属的位置。可获得影象的时间取决于靶向性分子的分布曲线,例如大多数肽会很快定位,使得在3小时之内便可获得影象,通常在1小时之内即可。在一具体实施方案中,通过静脉注射.施用本发明偶联于肽靶向性分子GTKPPR的螯合剂的盐水溶液,对病灶炎症部位进行造影。
下述实施例用于说明本发明的一些实施方案。实施例1-制备肽-螯合剂共轭物
N,N-二甲基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg
N,N-二甲基Gly-Thr-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg和
肌氨酸-Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg
使用FMOC化学法通过固相肽合成技术制备标题共轭物单链肽,使用应用生物系统433A肽合成仪(Foster City,CA)在预先接有FMOC-精氨酸的2-甲氧基-4-烷氧基苯甲醇树脂(Sasrin Resin,Bachem生命科学公司,费城)上进行合成。在链延伸的适当步骤中掺入衍生的氨基酸残基S-乙酰氨基甲基半胱氨酸(Bachem)、N,N-二甲基甘氨酸(Sigma化学公司,St.Louis.MO)和肌氨酸。
在加入最后一个残基N,N-二甲基甘氨酸或肌氨酸后,将肽树脂在真空条件下过夜干燥,并在室温下将9.5mL三氟乙酸(TFA),0.5ml水、0.5ml茴香硫醚和0.25ml 2-乙二硫醇的冷却溶液(每100mg肽树脂1ml)与肽树脂混合1.5至2小时,使肽从树脂上解离。过滤除去树脂,并用1-3mL TFA洗涤,得到6-8mL澄清的黄色液体。将此液体缓慢地滴入50ml锥形聚丙烯离心管中的30-35ml冷叔丁醚中,生成白色沉淀。0℃以7000rpm将该沉淀离心5分钟(Sorvall RT6000,Dupont),倾倒出上清液,用叔丁醚再洗涤两次。真空下干燥后,将该沉淀溶解于水中。在丙酮-干冰中冷冻溶液并将其冷冻干燥过夜。将所得白色粉末溶解于水,通过0.45μm注射过滤器(Gelman Acrodisc3CR PTFE)过滤,用C18柱(Waters RCM 25×10)反相HPLC(Beckman System Gold)进行纯化,以1%TFA水溶液为缓冲液A,1%TFA乙腈溶液为缓冲液B。用100∶0的缓冲液A:缓冲液B平衡柱子,以1mL/min在25分钟内线性梯度洗脱柱子至50%缓冲液B。级分在HPLC上进行再分析,并按匹配曲线收集级分。在丙酮-干冰中冷冻纯级分,并冷冻干燥12小时,得到白色粉末。实施例2-制备肽-螯合剂共轭物
N,N-二苄基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg
N,N-二乙基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg
使用FMOC化学法通过固相肽合成技术制备标题共轭物单链肽,使用应用生物系统433A肽合成仪(Foster City,CA)在预先载有FMOC-精氨酸的2-甲氧基-4-烷氧基苯甲醇树脂(Sasrin Resin,Bachem生命科学公司,费城)上进行合成。在链延伸的适当步骤中掺人衍生的氨基酸残基:S-乙酰氨基甲基-半胱氨酸(Bachem)、N,N-二乙基甘氨酸和N,N-二苄基甘氨酸。
用下述方法合成衍生的氨基酸残基N,N-二苄基甘氨酸:
在装有磁力搅拌子的烧瓶中,将溴乙酸(5.00g,35.99mmol)溶解于CH2Cl2,冷却至0℃,并加入二苄胺(8.31ml,43.79mmol)。反应混合物在O℃搅拌1小时,并温热至室温,然后在30-40℃之间加热12小时。将混合物溶液冷却至室温,减压条件下蒸发掉CH2Cl2,然后用热乙醇洗涤,并真空干燥得到白色固体残余物(71.2%产率)。
用下面的方法合成衍生的氨基酸残基N,N-二乙基甘氨酸:
在烧瓶中,向二乙胺(35mL)中加入氯乙酸(5.00g,52.91mmol),室温搅拌12小时,然后加热回流72小时。将反应混合物冷却至室温,并以HCl中和,浓缩使体积减小。然后力入乙酸乙酯和乙醇,过滤所得的白色沉淀并真空干燥,得到1.74g(25%产率)产物。
实施例3-标记肽-螯合剂共轭物
N,N-二甲基Gly-Ser-Cys(Acm)-GTKPPR
N,N-二甲基Gly-Thr-Cys(Acm)-GTKPPR
N,N-二乙基Gly-Ser-Cys(Acm)-GTKPPR
N,N-二苄基Gly-Ser-Cys(Acm)-GTKPPR和
肌氨酸Ser-Cys(Acm)-GTKPPR
重新制备实施例1和2的共轭物(200μl,1mg/ml盐水),然后将其与100μl高锝酸盐(10mCi)和100μl葡糖酸亚锡(50μg氧化亚锡和1mg葡糖酸钠)一起注射入3ml的真空容器。将此试管置于沸水浴中12分钟,然后通过Whatman PVDF注射过滤器过滤,收集被标记的共轭物溶液,进一步用盐水将其稀释,制得可注射用溶液(2Mbq/ml),通过HPLC(Beckman)从(20μl)样品中(在稀释前)分离该共轭物,通过测量放射活性确定标记率(labeling yield)。
共轭物 标记率
N,N-二甲基Gly-Ser-Cys(Acm)-GTKPPR >94%
N,N-二甲基Gly-Thr-Cys(Acm)-GTKPPR >94%
N,N-二乙基Gly-Ser-Cys(Acm)-GTKPPR 85.4%
N,N-二苄基Gly-Ser-Cys(Acm)-GTKPPR 98.9%
肌氨酸Ser-Cys(Acm)-GTKPPR 90.3%
除肌氨酸-Ser-Cys(Acm)-GTKPPR外每种结合物均出现单一峰,且标记率高于85%。标记24小时后,再在HPLC上重新分析N,N-二甲基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg,没有发现降解或辐解产物。实施例4-共轭物的体内造影和生物分布
按下述方法进行大鼠炎症研究。在造影前24小时,用酵母聚糖(25mg),一种酵母细胞壁悬液,对2只雄性Wistar大鼠(CharlesRiver,200-250g)肌内注射入其左后腿。1天后可肉眼观察到腿部的炎症病灶。将1mg.(约0.7μmol)螯合剂-肽共轭物溶解于50μl二甲亚砜中,并加入到乙醇-水混合物(1∶1,200μl)中。加入Tc-99m酒石酸盐(约400MBq)等份溶液,100℃时进行转螯合作用(transchelation)20分钟。通过Sep Pak柱洗脱纯化Tc-99m标记的共轭物,然后用盐水稀释制得含约100μCi(3.7MBq)活性的可注射用制剂(200μl)。
用茄醇(40至50mg/kg)麻醉大鼠,然后通过尾静脉注射被标记的共轭物溶液(200μl)。需要连续全身闪烁扫描30分钟。然后超剂量麻醉杀死大鼠,称量器官、尿、血、已发炎的肌肉(左腿)和未发炎的肌肉(右腿)和炎症渗出物(液体)样品,根据器官不同在孔型γ计数器或在γ剂量校准器中计数。假设血量占体重的8%,以此为依据来计算剂量。下表1所示的共轭物的结果为两只大鼠的平均值,并以尾中残余剂量进行了修正。
与其它已知炎症造影剂如Ga-67、99mTc-IgG、111In-WBC和99mTc-Nanocoll相比,两种共轭物均给出了极好的闪烁扫描影象,通过测到的靶与背景间的高比率(发炎的:未发炎的肌肉)表明了这一点。该共轭物比已知试剂的造影速度快得多,且呈现优越的生物分布性。此外非靶器官如肝脏和胃肠道显示出很低的积累量。
造影剂 | 发炎的:未发炎的 | 体液:血 | 尿(剂量百分数) | 肝(剂量百分数) | 胃肠道(剂量百分数) |
N,N-二甲基Gly-Ser-Cys(Acm)-GTKPPR-OHN,N-二甲基Gly-Thr-Cys(Acm )-GTKPPR-OHN,N-二苄基Gly-Ser-Cys(Acm)-GTKPPR-OH | 5.34.63.7 | 1.91.60.4 | 63.568.555.1 | 2.42.42.3 | 2.82.57.5 |
67Ga99mTc-IgG111In-WBC99mTc-Nanocoll | 2.52.81.53.3 | 0.10.030.10.2 | 5.51.20.20.8 | 26.517.636.966.7 | 8.40.73.62.1 |
Claims (30)
其中
X是一直链或支链的、饱和或不饱和C1-4烷基链,该烷基链可任选地插入一个或两个选自N、O和S的杂原子;可任选地被至少一个选自卤素、羟基、氨基、羧基、C1-4烷基、芳基和C(O)Z的基团取代;
Y是H或X定义的取代基;
X和Y一起形成一个5-至8-元的饱和或不饱和杂环,该杂环可任选地被至少一个选自卤素、羟基、氨基、羧基、氧代、C1-4烷基、芳基和C(O)Z的基团取代;
R1至R4各自独立地选自H;羧基;C1-4烷基;被一个选自羟基、氨基、巯基、卤素、羧基、C1-4烷氧羰基和氨基羰基的基团取代的C1-4烷基;除脯氨酸外的D-或L-氨基酸的α碳侧链;和C(O)Z;
R5和R6各自独立地选自H;羧基;氨基;C1-4烷基;被羟基、羧基或氨基取代的C1-4烷基;和C(O)Z;
R7选自H和硫保护基;及
Z选自羟基、C1-4烷氧基和一个靶向性分子。
2.根据权利要求1的化合物,其中R1、R2、R4、R5和R6为氢。
3.根据权利要求1的化合物,其中X和Y各自独立地选自C1-4烷基和芳基取代的C1-4烷基。
4.根据权利要求1的化合物,其中R3选自羟甲基和1-羟乙基。
5.根据权利要求1的化合物,其中Y独立地为X定义的取代基。
6.根据权利要求5的化合物,其中X和Y为选自甲基、乙基和苄基的相同基团。
7.根据权利要求5的化合物,其中R3选自羟甲基和1-羟乙基。
8.根据权利要求5的化合物,其中R1、R2、R4、R5和R6为氢。
9.根据权利要求1的化合物,其中Z为靶向性分子。
10.根据权利要求9的化合物,其中靶向性分子是肽。
11.根据权利要求10的化合物,其中肽包含3个或多个氨基酸残基。
12.根据权利要求11的化合物,其中肽包含序列TKPPR。
13.根据权利要求12的化合物,其中肽包含序列Gly-Thr-Lys-Pro-Pro-Arg-OH。
14.根据前述任一权利要求的化合物,呈与金属放射性核素或其氧化物或氮化物配合的形式。
15.根据权利要求14的化合物,其中所述金属放射性核素选自99mTc、64Cu、67Cu、97Ru、105Rh、109Pd、186Re、188Re、198Au、199Au、203Pb、212Pb和212Bi。
16.根据权利要求14的化合物,其中所述金属放射性核素选自99mTc、186Re和188Re。
17.根据权利要求14的化合物,其中所述金属放射性核素为99mTc。
其中
X是一直链或支链、饱和或不饱和C1-4烷基链,该烷基链可任选地插入一个或两个选自N、O和S的杂原子;且可任选地被至少一个选自卤素、羟基、氨基、羧基、C1-4烷基、芳基和C(O)Z的基团取代;
Y是H或X定义的取代基;
X和Y可一起形成一个5-至8-元的饱和或不饱和杂环,该杂环可任选地被至少一个选自卤素、羟基、氨基、羧基、氧代、C1-4烷基、芳基和C(O)Z的基团取代;
R1至R4各自独立地选自H;羧基;C1-4烷基;被一个选自羟基、氨基、巯基、卤素、羧基、C1-4烷氧羰基和氨基羰基的基团取代的C1-4烷基;除脯氨酸外的D-或L-氨基酸的α碳侧链;和C(O)Z;
R5和R6各自独立地选自H;羧基;氨基;C1-4烷基;被羟基、羧基或氨基取代的C1-4烷基;和C(O)Z;
Z选自羟基、C1-4烷氧基和一个靶向性分子;和
M是一金属放射性核素或其氧化物或氮化物。
19.根据权利要求18的化合物,其中M选自99mTc、64Cu、67Cu、97Ru、105Rh、109Pd、186Re、188Re、198Au、199Au、203Pb、212Pb和212Bi及其氧化物或氮化物。
20.根据权利要求18的化合物,其中M选自99mTc、186Re和188Re及其氧化物或氮化物。
21.根据权利要求18的化合物,其中M是99mTc或其氧化物或氮化物。
22.一种探测靶向性分子在哺乳动物体内位置的方法,包括施用诊断有效量的权利要求14的化合物,其中Z是靶向性分子。
23.根据权利要求22的方法,其中所说的金属放射性核素为99mTc。
24.一种在哺乳动物体内对病灶炎症部位进行造影的方法,包括施用诊断有效量的权利要求10的化合物,该化合物呈与金属放射性核素或其氧化物或氮化物配合的形式。
25.根据权利要求24的方法,其中所述金属放射性核素是99mTc。
26.一种在哺乳动物体内对病灶炎症部位进行造影的方法,包括施用有效量的权利要求12的化合物,该化合物呈与金属放射性核素或其氧化物或氮化物配合的形式。
27.根据权利要求26的方法,其中所说金属放射性核素为99mTc。
28.根据权利要求1的化合物,它选自
N,N-二甲基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg-OH;
N,N-二甲基Gly-Thr-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg-OH;
N,N-二乙基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg-OH;和
N,N-二苄基Gly-Ser-Cys(Acm)-Gly-Thr-Lys-Pro-Pro-Arg-OH。
29.根据权利要求28的化合物,呈与金属放射性核素或其氧化物或氮化物配合的形式。
30.根据权利要求29的化合物,其中所述金属放射性核素为99mTc。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/279,155 US5662885A (en) | 1994-07-22 | 1994-07-22 | Peptide derived radionuclide chelators |
US08/279,155 | 1994-07-22 |
Publications (1)
Publication Number | Publication Date |
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CN1158133A true CN1158133A (zh) | 1997-08-27 |
Family
ID=23067872
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN95195127A Pending CN1158133A (zh) | 1994-07-22 | 1995-04-28 | 肽衍生的放射性核素螯合剂 |
Country Status (11)
Country | Link |
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US (3) | US5662885A (zh) |
EP (1) | EP0772628B1 (zh) |
JP (1) | JP3753734B2 (zh) |
CN (1) | CN1158133A (zh) |
AT (1) | ATE194845T1 (zh) |
AU (1) | AU700772B2 (zh) |
CA (1) | CA2194551A1 (zh) |
DE (1) | DE69518083T2 (zh) |
HU (1) | HUT77137A (zh) |
NO (1) | NO970273L (zh) |
WO (1) | WO1996003427A1 (zh) |
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-
1994
- 1994-07-22 US US08/279,155 patent/US5662885A/en not_active Expired - Lifetime
-
1995
- 1995-04-28 WO PCT/CA1995/000249 patent/WO1996003427A1/en not_active Application Discontinuation
- 1995-04-28 AT AT95916539T patent/ATE194845T1/de not_active IP Right Cessation
- 1995-04-28 CN CN95195127A patent/CN1158133A/zh active Pending
- 1995-04-28 DE DE69518083T patent/DE69518083T2/de not_active Expired - Lifetime
- 1995-04-28 US US08/612,842 patent/US5976495A/en not_active Expired - Lifetime
- 1995-04-28 AU AU23011/95A patent/AU700772B2/en not_active Ceased
- 1995-04-28 EP EP95916539A patent/EP0772628B1/en not_active Expired - Lifetime
- 1995-04-28 JP JP50532396A patent/JP3753734B2/ja not_active Expired - Fee Related
- 1995-04-28 HU HU9700196A patent/HUT77137A/hu unknown
- 1995-04-28 CA CA002194551A patent/CA2194551A1/en not_active Abandoned
-
1996
- 1996-08-28 US US08/703,988 patent/US5780006A/en not_active Expired - Lifetime
-
1997
- 1997-01-21 NO NO970273A patent/NO970273L/no unknown
Also Published As
Publication number | Publication date |
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CA2194551A1 (en) | 1996-02-08 |
DE69518083T2 (de) | 2001-03-22 |
ATE194845T1 (de) | 2000-08-15 |
WO1996003427A1 (en) | 1996-02-08 |
HUT77137A (hu) | 1998-03-02 |
NO970273D0 (no) | 1997-01-21 |
AU700772B2 (en) | 1999-01-14 |
EP0772628A1 (en) | 1997-05-14 |
JP3753734B2 (ja) | 2006-03-08 |
US5662885A (en) | 1997-09-02 |
NO970273L (no) | 1997-03-12 |
JPH10502931A (ja) | 1998-03-17 |
EP0772628B1 (en) | 2000-07-19 |
US5780006A (en) | 1998-07-14 |
DE69518083D1 (de) | 2000-08-24 |
AU2301195A (en) | 1996-02-22 |
US5976495A (en) | 1999-11-02 |
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