CN110078767B - 一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物及其制备方法和应用 - Google Patents
一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物及其制备方法和应用 Download PDFInfo
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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Abstract
本发明公开了一种99mTc(HYNICNM)(tricine/TPPTS)配合物及制备方法和应用。通过配体HYNICNM的合成以及99mTc(HYNICNM)(tricine/TPPTS)配合物的制备两个步骤,得到99mTc(HYNICNM)(tricine/TPPTS)配合物。该配合物制备简便,具有乏氧选择性。在荷瘤小鼠肿瘤部位有较高的摄取与良好的滞留,肿瘤/非靶比值高,明显降低了肝肠等非靶器官的摄取,是性能优良的新型肿瘤乏氧显像剂。
Description
技术领域
本发明属于放射性药物技术领域,特别涉及一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物及其制备方法和应用。
背景技术
肿瘤严重威胁人类的健康,近些年来更是呈现出低龄化上升态的趋势,因而对肿瘤的早诊断早治疗对提高生存率和改善预后与生活质量有着重要意义。在实体瘤中,几乎都有乏氧细胞的存在,通常其比例随肿瘤体积增大而增加,肿瘤乏氧程度越高,肿瘤恶性可能性越大,而对放疗和某些化疗药物的灵敏性越差。因而检测肿瘤乏氧对制定治疗方案,提高治疗效果具有重要意义。目前有数种检测乏氧的方法,放射性核素显像是其中之一。利用放射性核素标记的肿瘤乏氧显影剂进行SPECT(Single photon emission computedtomography,单光子发射计算机断层术)和PET(Positron emission tomography,正电子发射计算机断层术)显像能在活体水平上整体、无创性地评价肿瘤的乏氧程度,在肿瘤诊断、分期、疗效监测及预后评估等方面的应用受到广泛关注,为临床选择及调整合理的肿瘤治疗方案提供客观依据,因此有着良好的临床应用前景。
肿瘤乏氧显像剂可以划分为硝基咪唑类和非硝基咪唑类,硝基咪唑类化合物被广泛应用于肿瘤乏氧检测中,其机理是:化合物的硝基在细胞内酶的作用下发生单电子还原,产生自由基阴离子,在正常细胞中,该中间体被氧化为原化合物,后扩散到细胞外,在乏氧细胞中,该中间体被进一步还原,产物与细胞内组分结合,并滞留在细胞内。由于99mTc具有适宜的半衰期(T1/2=6.02h)、140KeV的γ单光子发射等优点,且99Mo-99mTc发生器的推广应用使得99mTc放射性药物制备简单、可药盒化、质量可控,99mTc药物在核医学显像中占据主导地位,因此研制99mTc标记的肿瘤乏氧显像剂是国际上放射性药物化学研究的一个重要方向。目前尚无一种99mTc标记的肿瘤乏氧显像剂在临床中推广应用,因此研制新型的便于临床推广应用的99mTc标记的肿瘤乏氧显像剂具有重要的现实意义。
近年来,肼基尼古酰胺(HYNIC)作为一种常用双功能联接剂,其与99mTc配位时,可与协同配体一起制备合成稳定性好且放射化学纯度高的99mTc标记的HYNIC配合物,在99mTc放射性药物研究中引起广泛关注。在众多协同配体中,选择三羟甲基甘氨酸(tricine)和三苯基膦三磺酸钠(TPPTS)作为协同配体来制备99mTc标记的HYNIC配合物是一种行之有效的方法。例如99mTc(HYNIC-PEG2-FA)(tricine/TPPTS)作为叶酸受体类肿瘤显像剂被成功报道(Fang Xie,Chun Zhang,Qian Yu,et a1.Novel 99mTc radiolabeled folate complexeswith PEG linkers for FR-positive tumor imaging:synthesis and biologicalevaluation,RSC Adv.2014,4,32197-32206)。
综上所述,为研发性能优良的99mTc标记乏氧肿瘤分子探针,将硝基咪唑转化为含HYNIC的硝基咪唑衍生物(简称为:HYNICNM),然后和协同配体tricine/TPPTS与99mTc配位形成稳定的99mTc(HYNICNM)(tricine/TPPTS)配合物来探求新型肿瘤乏氧显像剂,具有重要的科学意义和广阔的应用前景,也是本领域面临的重要任务。
发明内容
本发明的目的是提供一种性能稳定、制备简便,用于肿瘤乏氧显像的锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物,同时提供其制备方法。
为了实现上述目的,本发明采用以下技术方案:一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物,其分子通式表达式为:99mTc(HYNICNM)(tricine/TPPTS),其结构式如下所示:
该结构式中:HYNICNM分子中肼基上的氮原子、共配体TPPTS中的磷原子以及tricine中的氧原子和氮原子与99mTc配位得到99mTc(HYNICNM)(tricine/TPPTS)配合物,其中n为大于和等于2的整数。
本发明还提供99mTc(HYNICNM)(tricine/TPPTS)配合物的制备方法,其制备步骤如下:
a:配体HYNICNM的合成:
称取适量含NHS活化酯的HYNIC腙类化合物1和含氨基的2-硝基咪唑类化合物2于25mL圆底烧瓶中,加入适量二甲基甲酰胺(DMF)溶解,然后加入适量三乙胺,加热回流反应4h;反应结束后减压蒸馏除去溶剂,柱层析纯化(二氯甲烷-甲醇)得到配体HYNICNM;
具体合成路线为:
b:99mTc(HYNICNM)(tricine/TPPTS)配合物的制备:
称取0.3mg HYNICNM配体于10mL的青霉素小瓶中,加入适量pH 5的醋酸钠缓冲液使其溶解,然后依次加入一定量TPPTS和tricine,适量SnCl2·2H2O,加入新鲜淋洗的Na99mTcO4溶液,沸水浴加热30min即可得到所述的99mTc(HYNICNM)(tricine/TPPTS)配合物。
本发明还提供99mTc(HYNICNM)(tricine/TPPTS)配合物的制备方法,其具体制备步骤如下:
a.配体HYNICNM的合成:
称取1mmol的化合物1和1mmol的化合物2于25mL圆底烧瓶中,加入10mL DMF溶解,然后加入3mmol的三乙胺,加热回流反应4小时;反应结束后减压蒸馏除去溶剂,柱层析纯化(二氯甲烷/甲醇=5:1)得到配体HYNICNM。
b.99mTc(HYNICNM)(tricine/TPPTS)配合物的制备
称取0.3mg HYNICNM配体于10mL的青霉素小瓶中,加入0.5mL pH 5的醋酸钠缓冲液使其溶解,然后依次加入5mg TPPTS,5mg tricine,40mg SnCl2·2H2O,加入2mL新鲜淋洗的Na99mTcO4溶液,沸水浴加热30min即可得到所述的99mTc(HYNICNM)(tricine/TPPTS)配合物。
通过上述方法制备的99mTc(HYNICNM)(tricine/TPPTS)配合物的放射化学纯度大于90%,为亲水性物质,体外稳定性良好。其在荷瘤小鼠肿瘤部位有较高的摄取与良好的滞留,肿瘤/肌肉和肿瘤/血比值好,在肝、肠、肺等非靶器官中的摄取值低,是性能优良的可用于肿瘤乏氧显像的新型SPECT分子探针。
实验表明,99mTc(HYNICNM)(tricine/TPPTS)配合物的性能如下:
1.99mTc(HYNICNM)(tricine/TPPTS)的鉴定
(1)99mTc(HYNICNM)(tricine/TPPTS)配合物薄层色谱(TLC)鉴定
薄层层析色谱(TLC)鉴定:使用双层析体系,体系一用聚酰胺薄膜作为支持体,用乙腈作为展开剂,体系二用滤纸作为支持体,用生理盐水作为展开剂,测定的层析结果见表1。
表1各组分的层析结果(Rf值)
由上述层析鉴定所测得的标记物的放射化学纯度大于90%。
(2)99mTc(HYNICNM)(tricine/TPPTS)配合物高效液相色谱(HPLC)鉴定
高效液相色谱(HPLC)鉴定:用C18反向柱,SCL-10AVP型高压液相色谱仪,A相为纯水,B相为甲醇,梯度为0-5min B相为0%,5-10min B相由0%变为20%,10-20min B相由20%变为50%,25min B相为0%。进样量为15μL,流速为1mL/min。测定的各组分的保留时间(Rt)分别为:99mTcO4 -:2.95min;99mTc-tricine:3.15min;99mTc(HYNICNM)(tricine/TPPTS):5.25min,所得的色谱结果表明有放射性主峰,99mTc(HYNICNM)(tricine/TPPTS)配合物的放射化学纯度大于90%。
2.99mTc(HYNICNM)(tricine/TPPTS)配合物的脂水分配系数的测定
取0.6mL pH 7.4的磷酸盐缓冲液(0.025mol/L)于2mL离心试管中,在离心试管中加入0.7mL正辛醇和0.1mL 99mTc(HYNICNM)(tricine/TPPTS)溶液,盖上塞子,充分摇匀,离心5min(5000r/min)。然后分别从有机相和水相中取出3×0.1mL,测定二相的放射性计数,并计算其分配系数P(P=有机相的放射性活度/水相的放射性活度),重复三次,测得log P=-3.03±0.08,表明99mTc(HYNICNM)(tricine/TPPTS)是一种水溶性物质。
3.99mTc(HYNICNM)(tricine/TPPTS)配合物的稳定性测定
将99mTc(HYNICNM)(tricine/TPPTS)配合物分别在室温下放置和37℃小鼠血清中放置6小时后测定其放射化学纯度,结果表明99mTc(HYNICNM)(tricine/TPPTS)配合物在室温下和37℃小鼠血清中放置6小时后放射化学纯度大于90%,说明其体外稳定性良好。
4.99mTc(HYNICNM)(tricine/TPPTS)配合物的体外细胞摄取实验
将S180细胞加入到含10%胎牛血清的DMEM培养液中使细胞浓度为2.0×106/mL。分别取出20mL上述S180细胞悬液,转移至2个反应瓶中,分别充入经水饱和的含有95%N2和5%CO2(乏氧),和含有95%空气和5%CO2(有氧)的混合气体,整个体系恒温于37℃水浴中。在乏氧体系中氧的浓度降至低于3ppm后,将0.2mL 99mTc(HYNICNM)(tricine/TPPTS)配合物(约7.4MBq)加入到细胞悬浮液中。在30、60、120和240min时分别取1.5mL细胞悬浮液样品,每个样品平行取5个200μL于离心管中,离心5min(2000r/min)以分离细胞和培养液,取180μL上清液,剩下的20μL含S180细胞的溶液分别用锝分析仪测量放射性计数,分别记作C180μL和C20μL。细胞的摄取百分比为:Uptake%=[C20μL-C180μL/9]/[C20μL+C180μL]×100%,结果见表2。
表2 99mTc(HYNICNM)(tricine/TPPTS)配合物的体外细胞摄取实验
体外细胞摄取实验表明,99mTc(HYNICNM)(tricine/TPPTS)配合物在乏氧细胞中的摄取值均高于其在有氧细胞中的摄取值,表明其具有乏氧选择性。
5.99mTc(HYNICNM)(tricine/TPPTS)配合物在荷瘤小鼠中的生物分布实验
从荷S180肉瘤模型小鼠的尾静脉注射0.10mL 99mTc(HYNICNM)(tricine/TPPTS)配合物溶液(约7.4×105Bq),注射后30、120和240min时断头处死小白鼠。取其心、肝、肺、肾、脾、骨、肠、胃、肌肉、血、肿瘤等有关组织和器官,擦净后称重,并在γ-Counter上测其放射性计数,计算各组织的每克百分注射剂量(%ID/g)。每个时相的小鼠数为5只。结果见表3。
表3 99mTc(HYNICNM)(tricine/TPPTS)配合物在S180小鼠中的生物分布
6.99mTc(HYNICNM)(tricine/TPPTS)在S180肿瘤小鼠SPECT扫描显像结果
从荷S180肉瘤模型小鼠的尾静脉注射99mTc(HYNICNM)(tricine/TPPTS)配合物溶液(约18.5MBq),2小时后,使用异氟烷麻醉。将小鼠俯卧固定,使用SPECT/CT进行显像。采用感兴趣区(region of interest,ROI)技术测定肿瘤和对侧正常部位的放射性计数,计算肿瘤和正常组织的摄取比值。SPECT显像结果表明99mTc(HYNICNM)(tricine/TPPTS)在肿瘤中有明显浓集,肿瘤和正常组织的摄取比值为5.61±1.02。
通过上述方法制备的99mTc(HYNICNM)(tricine/TPPTS)配合物放射化学纯度大于90%,为亲水性物质,体外稳定性良好。其在荷瘤小鼠肿瘤部位有较高的摄取与良好的滞留,肿瘤/肌肉和肿瘤/血比值好,在肝脏、肾脏、肺等非靶器官中的摄取值低,是一种性能优良的用于肿瘤乏氧显像的锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物,达到了发明目的。
具体实施方式
下面通过实施例详述本发明:一种锝-99m标记含肼基尼古酰胺基的2-硝基咪唑类配合物,其分子通式表达式为:99mTc(HYNICNM)(tricine/TPPTS),其结构式如下所示:
该结构式中:HYNICNM分子中肼基上的氮原子、共配体TPPTS中的磷原子以及tricine中的氧原子和氮原子与99mTc配位得到99mTc(HYNICNM)(tricine/TPPTS)配合物,其中n为大于和等于2的整数。
99mTc(HYNICNM)(tricine/TPPTS)配合物的制备方法,其制备步骤如下:
a.配体HYNICNM的合成:
称取0.440g含NHS活化酯的HYNIC腙类化合物1和0.156g含氨基的2-硝基咪唑类化合物2于25mL圆底烧瓶中,加入10mL DMF溶解,然后加入0.420mL三乙胺,加热回流反应4小时;反应结束后减压蒸馏除去溶剂,柱层析纯化(二氯甲烷/甲醇=5:1)得到配体HYNICNM0.305g,产率为66.6%。1H-NMR(400MHz,D2O)δ(ppm):8.49(s,1H),8.11-8.10(m,1H),7.88(d,J=7.9Hz,1H),7.67(d,J=7.8Hz,1H),7.60(dd,J=8.8Hz,2.4Hz,1H),7.36(t,J=7.4Hz,1H),7.27(t,J=7.7Hz,1H),7.22(d,J=1.2Hz,1H),6.96(d,J=1.2Hz,1H),6.88(d,J=8.9Hz,1H),4.45(t,J=5.7Hz,2H),3.54(s,2H);13C-NMR(100MHz,D2O)δ(ppm):168.23,157.38,147.08,144.52,140.53,140.34,137.36,131.53,131.25,129.21,128.47,127.80,126.86,126.58,120.19,107.48,49.44,38.99;HR-MS(ESI)for C18H16N7O6S:found458.0890,calcd 458.0888。
b.99mTc(HYNICNM)(tricine/TPPTS)配合物的制备
称取0.3mg HYNICNM配体于10mL的青霉素小瓶中,加入0.5mL pH 5的醋酸钠缓冲液使其溶解,然后依次加入5mg TPPTS,5mg tricine,40μg SnCl2·2H2O,加入2mL新鲜淋洗的Na99mTcO4溶液,沸水浴加热30min即可得到所述的99mTc(HYNICNM)(tricine/TPPTS)配合物。
Claims (3)
2.如权利要求1所述配合物的制备方法,其工艺步骤如下:
a:配体HYNICNM的合成:
称取适量含NHS活化酯的HYNIC腙类化合物1和含氨基的2-硝基咪唑类化合物2于25mL圆底烧瓶中,加入适量二甲基甲酰胺溶解,然后加入适量三乙胺,加热回流反应4h;反应结束后减压蒸馏除去溶剂,柱层析纯化得到配体HYNICNM;
具体合成路线为:
b:99mTc(HYNICNM)(tricine/TPPTS)配合物的制备:
称取一定量的HYNICNM配体于10mL的青霉素小瓶中,加入适量pH 5的醋酸钠缓冲液使其溶解,然后依次加入一定量TPPTS和tricine,适量SnCl2·2H2O,加入新鲜淋洗的Na99mTcO4溶液,沸水浴加热30min即可得到所述的99mTc(HYNICNM)(tricine/TPPTS)配合物。
3.如权利要求1所述的99mTc标记的含HYNIC的硝基咪唑类配合物制备而成的肿瘤乏氧显像剂在核医学领域的应用。
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Address after: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee after: BEIJING NORMAL University Patentee after: Beijing Shihong Pharmaceutical Co., Ltd Address before: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee before: BEIJING NORMAL University Patentee before: Beijing Shihong drug development center |