CN110078768B - 锝-99m标记的含HYNIC的帕博西尼衍生物及制备方法和应用 - Google Patents
锝-99m标记的含HYNIC的帕博西尼衍生物及制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种99mTc(HYNICPBB)(tricine/TPPTS)配合物及制备方法和应用,通过配体HYNICPBB的合成及99mTc(HYNICPBB)(tricine/TPPTS)配合物的制备两个步骤,得到99mTc(HYNICPBB)(tricine/TPPTS)配合物。该配合物制备简单、放射化学纯度高、稳定性好,有较好的水溶性,在MCF‑7细胞中有一定的摄取,且摄取可以被帕博西尼显著抑制,表明其具有CDK4/6特异性。其在雌性荷MCF‑7肿瘤Balb/c裸鼠肿瘤部位有较高的摄取和滞留以及较好的瘤/肉比值,肝脏等非靶器官的摄取明显降低,可用于制备新型靶向CDK4/6的肿瘤显像剂。
Description
技术领域
本发明涉及99mTc标记的放射性药物化学和临床核医学技术领域,具体说是涉及到一种99mTc标记的含HYNIC的帕博西尼衍生物及制备方法和应用。
背景技术
目前,恶性肿瘤已经成为危害人类健康的主要杀手,最新全球癌症统计报告显示,2018年全球新增癌症病例1810万,960万人因癌症死亡,2015年中国癌症统计报告指出,中国癌症患者的五年存活率仅为36.9%,这是因为很多患者在诊断出疾病时,就已经发生了区域性或远距离的转移,因此,对癌症的早发现、早治疗对提高患者生存率、降低患者死亡率、减少患者痛苦以及节省治疗费用具有十分重要的意义。
肿瘤的一个重要特征是细胞的异常增殖,这是由于细胞周期失去正常调控所引起的。正常的细胞周期包括G1期、S期(DNA复制)、G2期和M期(有丝分裂)四个连续的阶段,当细胞没有接收到合适的增殖信号时,会处于休眠期(G0 期)。细胞从细胞周期的一个时期到下一个时期的转变受到多种酶和蛋白的精确调控,例如细胞周期蛋白依赖性激酶(CDKs)、细胞周期蛋白(cyclins)、成视网膜细胞瘤蛋白(pRb)以及转录因子E2F等。其中,CDK4/6在细胞周期从G1 期到S期的转变中起到重要作用,当细胞接收到增殖信号后,CDK4/6与cyclinD 结合形成复合物,该复合物使得pRb磷酸化,导致pRb与E2F形成的复合物被破坏,E2F被释放出来,通过与相应靶基因启动子上的结合位点相结合,启动靶基因的转录,促使细胞周期进入S期。当发生基因突变或染色体异位时,cyclin D-CDK4/6-INK4-pRb通路异常调控会被激活,引起细胞周期紊乱,进而引起细胞异常过度增殖。在很多恶性肿瘤中都存在CDK4/6的异常表达,因此CDK4/6 成为肿瘤诊断与治疗的一个重要靶点。
近年来一些高选择性CDK4/6抑制剂作为抗肿瘤药物的研究取得了快速进展。其中,帕博西尼(palbociclib)是筛选出的一种高选择性CDK4/6抑制剂,通过抑制CDK4/6对pRb的磷酸化作用,将细胞周期阻滞在G1期,从而抑制肿瘤细胞的增殖或诱导肿瘤细胞的凋亡。该药物2015年获得FDA批准,联合来曲唑用于治疗绝经期女性雌激素受体阳性(ER+)、人表皮生长因子受体2阴性 (HER2-)的绝经期女性晚期乳腺癌。
目前,放射性标记的CDK4/6抑制剂作为肿瘤显像剂的研究不多,Koehler 等人在2010年报道了两种124I标记的化合物([124I]CKIA和[124I]CKIB,Eur.J.Med. Chem.2010,45,727–737),并探究了其作为肿瘤显像剂的可能性,实验结果表明,这两种标记物在大鼠体内的稳定性较差,因此并不适宜作为肿瘤显像剂。2018 年,本课题组设计合成了一类99mTc(CO)3核标记的含有异腈基团的帕博西尼衍生物,并已申请国家发明专利(专利申请号:201811275057.7)。该类配合物在雌性荷MCF-7肿瘤小鼠肿瘤部位有较高的摄取,肿瘤/肌肉比值也较好,但是其在肝脏等非靶器官的摄取很高(注射2h后,肝脏的每克百分注射剂量(%ID/g)达到 50%左右。
基于以上背景,本发明以商品化的帕博西尼为原料,对其进行结构修饰,在分子中引入HYNIC配位基团,得到含有HYNIC基团的帕博西尼衍生物配体,然后将其与N-三(羟甲基)甲基甘氨酸(tricine)和三苯基膦三间磺酸钠(TPPTS) 等水溶性共配体一起进行99mTc标记,探求水溶性更强、非靶器官摄取更低的新型靶向CDK4/6的SPECT肿瘤显像剂,具有重要的科学研究和应用开发价值。
发明内容
本发明的目的是提供一种放射化学纯度高、稳定性好,应用在肿瘤显像领域的99mTc标记的含HYNIC的帕博西尼衍生物及其制备方法和应用。
为了达到上述目的,本发明采用以下技术方案:一种99mTc标记的含HYNIC 的帕博西尼衍生物,分子通式为99mTc(HYNICPBB)(tricine/TPPTS),其结构式如下所示:
该结构式中:HYNICPBB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(HYNICPBB)(tricine/TPPTS)。
99mTc(HYNICPBB)(tricine/TPPTS)的制备方法如下:
a.配体HYNICPBB的合成:
称取适量帕博西尼(palbociclib)、三乙胺和含NHS活化酯的HYNIC腙类化合物C于反应容器中,加入适量二氯甲烷,室温下反应6h,反应结束后减压蒸馏除去溶剂,柱层析纯化得到配体HYNICPBB;
具体合成路线为:
b.99mTc(HYNICPBB)(tricine/TPPTS)配合物的制备:
向反应瓶中加入适量tricine和TPPTS,加入适量生理盐水使其溶解,再加入适量SnCl2·2H2O,然后加入含有10μg HYNICPBB配体的DMF溶液和适量新鲜淋洗的99mTcO4 -溶液,100℃下反应30min,即得到本发明所述的99mTc(HYNICPBB)(tricine/TPPTS)配合物。
通过上述方法制备的99mTc配合物放射化学纯度大于90%,99mTc(HYNICPBB)(tricine/TPPTS)配合物为水溶性物质,体外稳定性良好。其在 MCF-7细胞中有一定摄取,且摄取可以被帕博西尼显著性抑制,说明其与CDK4/6 是特异性结合,其在雌性荷MCF-7肿瘤Balb/c裸鼠肿瘤部位有较高的摄取,肿瘤/肌肉比值较高,肝脏摄取明显降低,有望成为新型靶向CDK4/6的肿瘤显像剂。
本发明所述的99mTc(HYNICPBB)(tricine/TPPTS)配合物的性能研究如下:
1.99mTc(HYNICPBB)(tricine/TPPTS)配合物的高效液相色谱(HPLC)鉴定:
高效液相色谱(HPLC)鉴定:Waters 600型高效液相色谱仪,Kromasil C18 反相柱(250×4.6mm),Gabi raytest放射性检测器。淋洗梯度见表1(A相为含0.1%TFA的水,B相为含0.1%TFA的乙腈),流速为1mL/min。99mTc标记的共配体99mTc(tricine/TPPTS)为多组分物质,各组分的保留时间均小于5.00min,而99mTc(HYNICPBB)(tricine/TPPTS)配合物的保留时间为14.00min。所得的色谱结果表明有一放射性主峰,99mTc(HYNICPBB)(tricine/TPPTS)配合物的放射化学纯度大于90%。
表1配合物的梯度洗脱条件
2.99mTc(HYNICPBB)(tricine/TPPTS)配合物的体外稳定性测定:
将99mTc(HYNICPBB)(tricine/TPPTS)配合物分别在室温下和在37℃小鼠血清中放置4h后测定其放射化学纯度,实验结果表明其在室温下和在37℃小鼠血清中放置4小时后放射化学纯度均大于90%,说明配合物的体外稳定性良好。
3.99mTc(HYNICPBB)(tricine/TPPTS)配合物的脂水分配系数测定:
将等体积的正辛醇和PBS缓冲液(pH=7.4,0.025mol/L)充分混匀,静置过夜待用。取1.0mL正辛醇和0.9mL PBS缓冲液于10mL离心管中,加入0.1mL 配合物溶液,充分摇匀,离心5min(8000r/min)。然后分别从有机相和水相中取出0.10mL,测定二相的放射性计数,并计算log P值(P=有机相的放射性活度/水相的放射性活度)。99mTc(HYNICPBB)(tricine/TPPTS)配合物的脂水分配系数(log P)为-2.951±0.078,说明其为水溶性物质。
4.99mTc(HYNICPBB)(tricine/TPPTS)配合物的体外细胞实验:
将MCF-7细胞接种于24孔板(2×105cells/孔),孔板置于5%CO2的37℃培养箱中过夜,使细胞呈单层贴壁状态。实验时,吸去培养基,并用0.5mL DMEM 培养基洗涤一次,抑制组加入0.1mL含60μM帕博西尼的DMEM培养基溶液, 30min后,摄取组和抑制组每孔加入0.1mL配合物溶液(约7.4kBq),再补加培养基使每孔的总体积为0.3mL,然后将孔板放入37℃培养箱中孵育。120min 后将溶液吸出,用冷的PBS(含0.2%BSA)洗涤两次,然后用0.5mL1M NaOH 溶液处理,再用γ-counter测定其计数。实验结果表明配合物在MCF-7细胞中有一定的摄取,且摄取可以被帕博西尼明显抑制,加入抑制剂后,99mTc(HYNICPBB)(tricine/TPPTS)配合物的细胞摄取降低了84.36%,说明其在 MCF-7细胞中的摄取是CDK4/6特异性的。
5.99mTc(HYNICPBB)(tricine/TPPTS)配合物在雌性荷MCF-7肿瘤Balb/c裸鼠体内的生物分布实验
将0.1mL配合物溶液尾静脉注射到雌性荷MCF-7肿瘤Balb/c裸鼠体内,分别在注射后1h和2h将小鼠断头处死。取其血、心、肝、肺、肾、肌肉、骨、肿瘤等有关组织和器官,擦净后称重,并用γ-counter测其放射性计数,计算各组织的每克百分注射剂量(%ID/g)。每个时相的小白鼠数为3只,生物分布实验的结果如表2所示:
表2 99mTc(HYNICPBB)(tricine/TPPTS)配合物在荷MCF-7肿瘤Balb/c裸鼠体内的生物分布实验结果(x±s,%ID/g)
从表2可以看出,99mTc(HYNICPBB)(tricine/TPPTS)配合物在注射后1h和2 h在肿瘤中都较高的摄取且具有较高的瘤/肉比值,而且在肝脏等非靶器官的摄取明显降低,表明其可以作为新型肿瘤显像剂。
6.99mTc(HYNICPBB)(tricine/TPPTS)配合物在荷MCF-7肿瘤Balb/c裸鼠的 SPECT/CT显像实验:
将制备好的99mTc(HYNICPBB)(tricine/TPPTS)配合物(0.1mL,18.5MBq)尾静脉注射到雌性荷MCF-7肿瘤Balb/c裸鼠体内,2h后进行显像实验。SPECT/CT 显像结果表明其在肿瘤部位有明显浓集,同等体积的肿瘤区域与对侧肌肉区域的放射性计数比(regions ofinterest,ROI)为3.94±0.28,肿瘤部位与肌肉区分明显。为了进一步验证配合物在肿瘤部位的摄取是CDK4/6特异性的,还进行了显像抑制实验,提前30min注射抑制剂帕博西尼,再注射99mTc(HYNICPBB)(tricine/TPPTS)配合物,2h后进行显像实验,结果表明注射抑制剂后在肿瘤部位看不到明显放射性浓集,ROI比值降低为0.95±0.18,与未注射抑制剂时有显著性差异,表明99mTc(HYNICPBB)(tricine/TPPTS)配合物在肿瘤部位的摄取是CDK4/6特异性的。
具体实施方式:
下面通过实施例详述本发明:一种99mTc标记的含HYNIC的帕博西尼衍生物,分子通式为99mTc(HYNICPBB)(tricine/TPPTS),其结构式如下所示:
该结构式中:HYNICPBB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(HYNICPBB)(tricine/TPPTS)。
99mTc(HYNICPBB)(tricine/TPPTS)的具体制备步骤如下:
a.配体HYNICPBB的合成:
称取447mg帕博西尼和440mg化合物C于100mL圆底烧瓶中,加入200 μL三乙胺和30mL二氯甲烷,室温下反应6h。反应结束后,旋蒸除去溶剂,粗产物使用硅胶柱层析(二氯甲烷:甲醇=10:1)分离纯化,干燥后得化合物 HYNICPBB。1H NMR(400MHz,DMSO-d6):δ11.26(s,1H),10.12(s,1H),8.98(s, 1H),8.91(s,1H),8.22(dd,J=2.3,0.8Hz,1H),8.05(d,J=2.9Hz,1H),7.99(dd,J =7.8,1.4Hz,1H),7.86(d,J=9.0Hz,1H),7.75(dd,J=7.7,1.5Hz,1H),7.70(dd,J =8.6,2.3Hz,1H),7.47(dd,J=9.1,3.0Hz,1H),7.35-7.30(m,1H),7.28-7.21(m, 2H),5.78(p,J=8.9Hz,1H),3.66(m,4H),3.19(m,4H),2.38(s,3H),2.26(s,3H),2.24-2.15(m,2H),1.90-1.79(m,2H),1.74(m,2H),1.61-1.49(m,2H).13C NMR (100MHz,DMSO-d6):δ203.04,168.25,161.28,159.00,158.78,158.39,155.28, 148.19,146.36,145.34,143.69,142.62,141.36,138.12,136.53,132.56,129.83, 129.27,128.13,127.31,125.96,125.66,122.17,115.51,107.16,106.17,53.49,49.25, 49.13,31.83,28.10,25.67,14.16.HRMS(m/z):749.2618(calc.749.2618 C37H37N10O6S[M-Na]-).
b.99mTc(HYNICPBB)(tricine/TPPTS)配合物的制备:
在青霉素小瓶中加入20mg tricine和5mg TPPTS,加入0.2mL生理盐水使其溶解,再加入25μg SnCl2·2H2O,然后加入10μL含有配体HYNICPBB的DMF 溶液(1mg/mL)和0.5mL新鲜淋洗的99mTcO4 -溶液,100℃下反应30min,即得到本发明所述的99mTc(HYNICPBB)(tricine/TPPTS)配合物。
Claims (3)
2.如权利要求1所述99mTc标记的含HYNIC的帕博西尼衍生物的制备方法,其制备步骤如下:
a.配体HYNICPBB的合成:
称取适量帕博西尼、三乙胺和含NHS活化酯的HYNIC腙类化合物C于反应容器中,加入适量二氯甲烷,室温下反应6h,反应结束后减压蒸馏除去溶剂,柱层析纯化得到配体HYNICPBB;
具体合成路线为:
b.99mTc(HYNICPBB)(tricine/TPPTS)配合物的制备:
向反应瓶中加入适量tricine和TPPTS,加入适量生理盐水使其溶解,再加入适量SnCl2·2H2O,然后加入含有10μg HYNICPBB配体的DMF溶液和适量新鲜淋洗的99mTcO4 -溶液,100℃下反应30min,即得到所述的99mTc(HYNICPBB)(tricine/TPPTS)配合物。
3.如权利要求1所述的99mTc标记的含HYNIC的帕博西尼衍生物制备而成的肿瘤显像剂在核医学显像领域的应用。
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