CN106008636B - 锝‑99m标记葡萄糖氨荒酸盐配合物及制备方法和应用 - Google Patents
锝‑99m标记葡萄糖氨荒酸盐配合物及制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种锝‑99m标记葡萄糖氨荒酸盐配合物及制备方法和应用，配合物以[99mTcN]2+核为中心核，两个1GDTC分子中的4个硫原子与99mTc配位，通过配体1GDTC的合成及99mTcN(1GDTC)2配合物的工艺制备而获得。该配合物的放射化学纯度高，稳定性好，在荷瘤小鼠肿瘤中有较高的摄取值及肿瘤/肌肉和肿瘤/血的比值，制备简便、亲肿瘤性能优良，可以作为一种新型的肿瘤显像剂推广应用。
Description
技术领域
本发明涉及放射性药物化学和临床核医学技术领域，具体涉及到一种锝-99m标记葡萄糖氨荒酸盐配合物及制备方法和应用。
背景技术
癌症已成为威胁人类健康的重要杀手，早发现、早治疗被认为是提高癌症患者生存率的重要手段。核医学显像技术能够早期地(甚至在发生病理学改变之前)在分子层面对肿瘤进行诊断，且具有无创性、灵敏度高等特点，目前已经成为肿瘤诊断的重要手段之一。
糖酵解是肿瘤细胞内葡萄糖代谢的主要途径，恶性肿瘤细胞增殖迅速，对葡萄糖的需求量远高于正常细胞，而肿瘤细胞膜上表达大量的葡萄糖转运蛋白。D-葡萄糖类似物结构与D-葡萄糖类似，也可被葡萄糖转运蛋白转运，被代谢旺盛的肿瘤细胞摄取。其被放射性核素标记后，可通过PET、SPECT进行体外探测，用于肿瘤诊断、分期、治疗及疗效评价。18F-氟代脱氧葡萄糖([18F]FDG)是目前临床应用最广泛的肿瘤显像剂。目前在中国SPECT比PET使用更为普及，同时锝-99m具有核素性质良好、廉价易得等优点，因此研究锝-99m标记葡萄糖类肿瘤显像剂具有广阔的应用前景,临床意义和社会效益巨大。
锝-99m标记在本技术领域常写为99mTc标记，目前99mTc标记葡萄糖类似物中只有99mTc-ethylenedicysteine-deoxyglucose(简称99mTc-ECDG)研究较为深入，目前已进入三期临床研究阶段，但其存在着肿瘤的绝对摄取值不高、血本底较高且清除较慢等不足，因此有必要探索生物性能更为优良的99mTc标记的葡萄糖类肿瘤代谢显像剂。
[99mTcN]2+三重键具有很高的化学稳定性，其相应配合物具有特殊的生物分布性质，[99mTcN]2+放射性药物的研究成为99mTc放射性药物的研究热点。[99mTcN]2+中间体可以通过SDH(丁二酰二酰肼，H2NNHCOCH2CH2CONHNH2)药盒在室温下制备而得，这为[99mTcN]2+放射性药物在临床的推广应用打开了方便之门。
为研发性能优良的99mTc标记葡萄糖类肿瘤显像剂，本发明对葡萄糖的C1位进行结构修饰，将葡萄糖巧妙转化为葡萄糖氨荒酸盐(简称为：1GDTC)，然后利用氨荒酸盐配体中的硫原子与99mTcN核配位，从而形成稳定的99mTcN(1GDTC)2配合物。
发明内容
本发明的目的是提供一种制备简便且亲肿瘤性能优良的99mTcN(1GDTC)2配合物，同时还提供其制备方法。
为了达到上述目的，本发明采用以下技术方案：一种99mTcN(1GDTC)2配合物，其结构式为：
该结构式中：以[99mTcN]2+核为中心核，两个1GDTC分子中的4个硫原子与99mTc配位，得到99mTcN(1GDTC)2配合物。
99mTcN(1GDTC)2配合物的制备方法如下：
a:配体1GDTC的合成：
合成路线为：
取适量1-溴-D-葡萄糖四乙酸酯和NaN3于烧瓶中，加入适量甲醇，加热回流反应过夜，减压蒸馏除去溶剂，加入二氯甲烷，用水洗涤，无水MgSO4干燥有机相，减压蒸馏除去溶剂，乙醚重结晶得到1-叠氮-D-葡萄糖四乙酸酯；取1-叠氮-D-葡萄糖四乙酸酯和三苯基膦于烧瓶中，加入四氢呋喃，加热回流反应3h，加入水，继续反应1h；减压蒸馏除去溶剂，柱层析纯化(石油醚-乙酸乙酯)，得到1-氨基-D-葡萄糖四乙酸酯，将1-氨基-D-葡萄糖四乙酸酯溶于甲醇中，加入适量KOH，室温下搅拌反应4h；反应结束之后，加入1mol/L HCl调节溶液pH至中性，减压蒸馏除去溶剂，加入乙醇，过滤并收集滤液，除去溶剂得到粗产物；将所有产物溶于水中，加入等量的KOH，冰水浴条件下滴加过量的CS2，继续置于冰水浴中反应2h；反应结束之后，减压蒸馏除去溶剂，用乙醇重结晶，得到浅黄色固体1GDTC；
b：99mTcN(1GDTC)2配合物的制备：
99mTcN(1GDTC)2配合物的制备采用配体交换反应，反应路线如下：
99mTcO4 -+SDH+SnCl2.2H2O+PDTA→[99mTcN]int 2+
[99mTcN]int 2++1GDTC→99mTcN(1GDTC)2
具体操作步骤为：将适量99mTcO4 -淋洗液加入到含有丁二酰二酰肼(SDH)、1,2-丙二胺四乙酸、SnCl2.2H2O的SDH冻干药盒中，充分摇匀使固体溶解，在室温下反应15min得到[99mTcN]2+中间体；将1mL浓度为1g/L的1GDTC水溶液加入到上述[99mTcN]2+中间体中，混匀后在室温下放置30min即得到所述99mTcN(1GDTC)2配合物。
上述所用的化学试剂均是市售商品，来源广泛，容易获得，而所述SDH冻干药盒可以从北京师宏药物研制中心购买获得。
通过上述方法制备的99mTcN(1GDTC)2配合物体外稳定性好，其放射化学纯度大于90％。
本发明生物分布数据比较：
对99mTcN(1GDTC)2、99mTcN(DGDTC)2(Junbo Zhang,Jialei Ren,Xiao Lin,XuebinWang.Synthesis and biological evaluation of a novel 99mTc nitridoradiopharmaceutical with deoxyglucose dithiocarbamate,showing tumor uptake[J],Bioorganic&Medicinal Chemistry Letters,2009,19:2752-2754)和99mTcN(TAGDTC)2配合物(Teli Liu,Qianqian Gan,Junbo Zhang,Zhonghui Jin,Weifang Zhang,YanyanZhang.Synthesis and biodistribution of novel 99mTcN complexes of glucosedithiocarbamate as potential probes for tumor imaging[J].MedChemComm,2016,DOI:10.1039/c6md00127k)在荷S180肉瘤小鼠体内注射2h后生物分布数据进行比较，结果如表1：
表1：99mTcN(1GDTC)2、99mTcN(DGDTC)2和99mTcN(TAGDTC)2配合物在荷S180肉瘤小鼠体内注射2h后的生物分布(X±S，％ID/g)
以上对比结果表明，99mTcN(1GDTC)2在肿瘤中的摄取值、肿瘤/肌肉和肿瘤/血的比值均为最高,在肾脏等非靶器官中的摄取值更低,可以作为一种新型葡萄糖类肿瘤显像剂在临床推广应用。
实验表明，99mTcN(1GDTC)2配合物的性能如下：
1.99mTcN(1GDTC)2配合物的薄层层析色谱法鉴定：
采用薄层层析色谱法(TLC)进行鉴定：以聚酰胺薄膜作为支持体，分别以乙腈和生理盐水为展开剂。测定的层析结果见表2。
表2各组分的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％。
2.99mTcN(1GDTC)2配合物的脂水分配系数的测定：
取0.98mL pH7.4的磷酸盐缓冲液(0.025mol/L)于10mL离心试管中，在离心试管中加入1.0mL正辛醇和0.02mL99mTcN(1GDTC)2配合物溶液,盖上塞子，充分摇匀，离心(5000r×5min)，然后分别从有机相和水相中各取出0.1mL，测定两相的放射性计数并计算logP值(P＝有机相的放射性活度/水相的放射性活度)，重复测定三次。99mTcN(1GDTC)2的脂水分配系数logP＝-1.06±0.01，说明其是一亲水性物质。
3.99mTcN(1GDTC)2配合物的稳定性测定：
将标记好的99mTcN(1GDTC)2配合物分别在室温下和在小鼠血清37℃条件下孵育不同时间(1、2、3、4、5、6小时)后测定其放射化学纯度，实验结果表明该配合物在室温和在小鼠血清37℃条件下放置6小时后其放射化学纯度均大于90％，说明其体外稳定性良好。
4.99mTcN(1GDTC)2配合物的细胞摄取实验：
向离心管内加入1mL细胞培养基溶液，一共8组，每组5个离心管，向第1组中加入0.1mL生理盐水作为控制组；向第2组中加入0.1mL浓度为10mg/mL的D-葡萄糖溶液；向第3组中加入0.1mL浓度为20mg/mL的D-葡萄糖溶液；向第4组中加入0.1mL浓度为10IU/mL的胰岛素溶液(5mmol/L的葡萄糖溶液配制)；向第5组中加入0.1mL浓度为20IU/mL的胰岛素溶液(5mmol/L的葡萄糖溶液配制)；向第6组中加入0.1mL 5mmol/L的葡萄糖溶液作为胰岛素组的控制组；向第7组中加入0.1mL浓度为100μmol/mL的细胞松弛B的溶液；向第8组中加入0.1mL浓度为200μmol/mL的细胞松弛B的溶液。然后向每个离心管内加入0.1mL 99mTcN(1GDTC)2的无糖培养基溶液(0.74MBq/mL),摇匀后在37℃条件下孵育2h。孵育结束之后，离心(10000r×5min)，用1mL PBS洗涤、离心，合并上清液，处理完后分别测定上清液和沉淀的放射性计数。再取出5个离心管，每个离心管内加入1mL不含细胞的培养基溶液和0.1mL99mTcN(1GDTC)2的无糖培养基溶液(0.74MBq/mL)，摇匀后在37℃条件下孵育2h，取出培养基，用1mL PBS洗涤、离心，移去上清液，测定离心管的残留放射性计数，将其作为空白。通过以下公式计算：
％Uptake＝(沉淀计数–空白)/(沉淀计数+上清液计数–空白)×100％
实验结果表明，加入不同浓度的D-葡萄糖后，99mTcN(1GDTC)2在S180肿瘤细胞中的摄取值均有所降低，当加入0.5mgD-葡萄糖后，细胞摄取值降低了61.29％。加入不同浓度的细胞松弛素B后，99mTcN(1GDTC)2在S180肿瘤细胞中的摄取值降低，当加入10μmol的细胞松弛素B之后，细胞摄取值降低了53.77％。加入不同浓度的胰岛素之后，99mTcN(1GDTC)2在S180肿瘤细胞中的摄取值均有所提高，当加入1IU的牛胰岛素后，细胞摄取值提高了84.20％。综合以上研究结果表明99mTcN(1GDTC)2在S180肿瘤细胞中的摄取与葡萄糖转运蛋白相关,与D-葡萄糖摄取机制类似。
5.99mTcN(1GDTC)2配合物在荷S180肉瘤小鼠模型中的生物分布实验：
从荷S-180肉瘤模型的昆明小鼠(雌性，体重约18-20g)的尾静脉注射0.10mL99mTcN(1GDTC)2配合物溶液(约3.7×105Bq)，注射后分别与0.5h、2h、4h断头处死，每个时相各5只。取其心、肝、肺、肾、脾、肠、肌肉、骨、血、肿瘤等有关组织和器官，擦净后称重，并用锝分析仪测定放射性计数。计算各组织的每克百分注射剂量(％ID/g)，结果见表3。
表3 99mTcN(1GDTC)2配合物在荷S180肉瘤小鼠模型中的生物分布(x±s,％ID/g)
6.99mTcN(1GDTC)2配合物在荷S180肉瘤小鼠体内的SPECT显像实验：
将0.1mL标记好的99mTcN(1GDTC)2(18.5MBq)从尾静脉注射到荷S180肉瘤模型的昆明小鼠(雌性，体重约18-20g)体内，4h后进行SPECT显像。SPECT显像结果表明99mTcN(1GDTC)2在肿瘤部位有明显浓聚，表明其可以作为一种性能优良的新型肿瘤显像剂。
具体实施方式：
下面通过实施例详述本发明：
99mTcN(1GDTC)2配合物的制备：
a.配体1GDTC的合成
第一步：
取3.73g 1-溴-D-葡萄糖四乙酸酯和1g NaN3于烧瓶中，加入80mL甲醇，加热回流反应过夜。减压蒸馏除去溶剂，加入50mL二氯甲烷，用水(2×50mL)洗涤，无水MgSO4干燥有机相，减压蒸馏除去溶剂，乙醚重结晶得到1-叠氮-D-葡萄糖四乙酸酯。取1.78g 1-叠氮-D-葡萄糖四乙酸酯和2g三苯基膦于烧瓶中，加入60mL四氢呋喃，加热回流反应3h，加入0.1mL水，继续反应1h。减压蒸馏除去溶剂，柱层析纯化(石油醚-乙酸乙酯)，得到1-氨基-D-葡萄糖四乙酸酯，产率：92％。1H NMR(400MHz,CDCl3):δ(ppm)5.18-5.23(t,J＝19.0Hz,1H),4.95-5.03(m,1H),4.77-4.82(t,J＝18.6Hz,1H),4.06-4.21(m,3H),3.66-3.67(d,J＝5.1Hz,1H),1.98-2.06(m,12H).13C NMR(100MHz,CDCl3):δ(ppm)170.48,170.10,169.36,156.29,100.81,79.22,71.91,71.32,68.39,65.99,61.84,49.75,46.63,45.43,43.82,30.33,27.14,26.25,20.70,20.66,20.52.IR(KBr)/cm-1：3412.22,1755.30,1735.04,1383.98,1263.43,1256.68,1245.10,1225.82,1212.31,1038.71.ESI-MS,[M+H2O]+:m/z＝366.0。
第二步：
将1.73g 1-氨基-D-葡萄糖四乙酸酯溶于50mL甲醇中，加入1.13g KOH，室温下搅拌反应4h。反应结束之后，加入1mol/L HCl调节溶液pH至中性，减压蒸馏除去溶剂，加入乙醇，过滤并收集滤液，除去溶剂得到粗产物。将所有产物溶于50mL水中，加入280mg KOH，冰水浴条件下滴加0.5mL CS2，继续置于冰水浴中反应2h。反应结束之后，减压蒸馏除去溶剂，用乙醇重结晶得到浅黄色固体1GDTC，产率：43％。1H NMR(400MHz,D2O):δ(ppm)5.48-5.50(d,J＝8.7Hz,1H),3.82-3.86(m,1H),3.65-3.70(m,1H),3.45-3.55(m,3H),3.34-3.40(m,1H).13C NMR(100MHz,D2O):δ(ppm)181.50,164.07,76.94,76.62,60.41,48.96,23.35.IR(KBr)/cm-1：3380,1577,1409,1340,1048,1017,649,621.ESI-MS,[M-H]-:m/z＝253.1。
b.99mTcN(1GDTC)2配合物的制备
向SDH药盒中加入37～370MBq新鲜的99mTcO4 -淋洗液，摇匀后室温放置15min后即得到[99mTcN]2+中间体。向上述[99mTcN]2+中间体中加入1mL浓度为1g/L的1GDTC水溶液，摇匀后在室温下反应30min，即得到本发明所述的99mTcN(1GDTC)2。
Claims (3)
1.一种99mTcN(1GDTC)2配合物，其结构式为：
该结构式中：以[99mTcN]2+核为中心核，两个1GDTC分子中的4个硫原子与99mTc配位，得到99mTcN(1GDTC)2配合物。
2.如权利要求1所述99mTcN(1GDTC)2配合物的制备方法，其工艺步骤如下：
a.配体1GDTC的合成：
合成路线为：
取适量1-溴-D-葡萄糖四乙酸酯和NaN3于烧瓶中，加入适量甲醇，加热回流反应过夜，减压蒸馏除去溶剂，加入二氯甲烷，用水洗涤，无水MgSO4干燥有机相，减压蒸馏除去溶剂，乙醚重结晶得到1-叠氮-D-葡萄糖四乙酸酯；取1-叠氮-D-葡萄糖四乙酸酯和三苯基膦于烧瓶中，加入四氢呋喃，加热回流反应3h，加入水，继续反应1h；减压蒸馏除去溶剂，柱层析纯化，得到1-氨基-D-葡萄糖四乙酸酯，将1-氨基-D-葡萄糖四乙酸酯溶于甲醇中，加入适量KOH，室温下搅拌反应4h；反应结束之后，加入1mol/L HCl调节溶液pH至中性，减压蒸馏除去溶剂，加入乙醇，过滤并收集滤液，除去溶剂得到粗产物；将所有产物溶于水中，加入等量的KOH，冰水浴条件下滴加过量的CS2，继续置于冰水浴中反应2h；反应结束之后，减压蒸馏除去溶剂，用乙醇重结晶，得到浅黄色固体1GDTC；
b.99mTcN(1GDTC)2配合物的制备：
99mTcN(1GDTC)2配合物的制备采用配体交换反应，反应路线如下：
99mTcO4 -+SDH+SnCl2.2H2O+PDTA→[99mTcN]int 2+
[99mTcN]int 2++1GDTC→99mTcN(1GDTC)2
具体操作步骤为：将适量99mTcO4 -淋洗液加入到含有丁二酰二酰肼(SDH)、1,2-丙二胺四乙酸、SnCl2.2H2O的SDH冻干药盒中，充分摇匀使固体溶解，在室温下反应15min得到[99mTcN]2+中间体；将1mL浓度为1g/L的1GDTC水溶液加入到上述[99mTcN]2+中间体中，混匀后在室温下放置30min即得到所述99mTcN(1GDTC)2配合物。
3.如权利要求1所述的99mTcN(1GDTC)2配合物在核医学显像领域制备肿瘤显像剂中的应用。
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