CN107674098B - 一类含芳基硼酸的99mTc配合物及其药盒配方和应用 - Google Patents
一类含芳基硼酸的99mTc配合物及其药盒配方和应用 Download PDFInfo
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Abstract
本发明提供一类含芳基硼酸的99mTc(III)配合物,其分子式为99mTcX(CDO)(CDOH)2B‑R。本发明化合物具有制备简单、价格低廉、标记率和放射化学纯度高、靶与非靶比值高、心脏摄取值高且滞留时间长等优点,可作为一种新型锝‑99m标记的心肌灌注显像剂应用在放射性药物化学和临床核医学技术领域中。
Description
技术领域
本发明涉及99mTc配合物,具体涉及一种含芳基硼酸的99mTc(III)配合物及制备所述配合物的药盒配方和应用。
背景技术
心血管疾病(CAD)是威胁人类健康最严重的疾病之一。在我国,CAD 的发病率以及死亡率均呈持续上升趋势。目前,估计全国有心血管病患病者 2.9亿,2012年,《中国心血管病报告2013》公布的资料显示:2012年心血管病死亡率为255/10万。估计每年约350万人死于心血管病。2012年心血管病在城市居民疾病死亡构成中占41.1%,在农村占38.7%,居各种疾病之首,高于肿瘤及其他疾病。
心血管疾病(CAD)是由冠状动脉粥样硬化引起冠状动脉逐渐狭窄导致。冠状动脉狭窄会导致冠状动脉血流量降低,使得心肌组织缺血,供氧量不足,引起心肌缺血甚至心肌梗塞。因此,在CAD形成的早期进行准确的诊断对CAD疾病的预防、诊断与治疗有重要的现实意义。
心肌灌注显像用于心脏病无创检查始于上世纪70年代,其巨大的诊断价值已在世界范围内被广泛接受,成为目前冠心病诊断、疗效评价以及预后判断的最重要的影像学方法之一。心肌灌注单光子发射计算机断层(SPECT) 显像技术是当前临床上用于冠心病检测的无创性灌注显像的主要方法,在评价心脏功能以及心肌灌注缺血区方面有重要意义。患有心血管疾病的患者,基本存在心肌血流量降低的情况,如果在负荷状态下的血流量明显低于静息状态,那么心肌灌注缺损区很有可能是由心肌缺血引起的。如果在负荷状态下的血流量与静息状态相当,那么心肌灌注缺损区很有可能是由心肌梗塞引起的。心肌灌注显像药物是心肌灌注显像技术的基石,放射性药物在心肌中摄取的比例能准确评估心肌灌注缺损的面积。心肌血流量的精确测定在评估心肌缺血区、心血管疾病的严重程度、心肌活力、心脏手术方案、术后恢复等方面有重要的临床意义。冠状动脉疾病(CAD)是造成早逝及永久性损伤的主要原因。冠状动脉的逐渐狭窄就会导致CAD疾病,并最终导致病人心肌缺血。晚期CAD患者中,较低的血流流速会引起心肌组织缺氧并难以维持心脏功能,最终导致心肌梗塞。心肌灌注显像(MPI)作为一种无创的通过放射性示踪剂检测CAD的手段能够评估心脏功能和血流灌注的缺损区。为了准确的评估心肌血流缺损区,放射性示踪剂在心肌组织中的摄取必须与心肌血流量呈线性关系。心肌血流量的精确测定在鉴定缺血心肌、评估CAD疾病严重程度和心肌活力以及确立手术治疗方案和必要性方面具有重要的临床意义。因此,一个性能完美的心肌灌注示踪剂应该具备以下特征:1)具有再分布性质;2)心肌初始摄取高且滞留好,且高血流流速时(0-5mL/min/g) 心肌摄取与血流量仍线性相关。99mTc-Sestamibi是目前核医学对CAD疾病诊断中常用的放射性示踪剂,但是一个主要的缺点就是首次提取率较低,当心肌血流量>2.5mL/min/g时心肌摄取值与局部心肌血流量缺乏线性关系。目前,在所有的99mTc标记的心肌灌注用放射性示踪剂中,99mTc-Teboroxime的首次通过率最高,但是心肌滞留较差,在注射后5min之后大约60%的放射性从心肌清除,当心肌血流量达到2.5mL/min/g时,心肌摄取值与局部血流量在注射后5min之内是呈线性关系的,不利于心肌活力评估。这些因素限制了99mTc-Teboroxime的临床使用。当今核医学寻找一种具有良好心肌滞留与生物性能的放射性示踪剂迫在眉睫。
发明内容
本发明的课题在于提供一类具有制备简单、价格低廉、标记率和放射化学纯度高、靶与非靶比值高、心脏摄取值高且滞留时间长等优点的含芳基硼酸的99mTc(III)配合物。
本发明的另一课题在于提供制备所述的含芳基硼酸的99mTc(III)配合物的药盒配方。
本发明的另一课题是提供所述的含芳基硼酸的99mTc(III)配合物在制备心肌灌注显像剂中的应用。
为解决上述课题,本发明主要采用以下技术方案:
1.一类含芳基硼酸的99mTc(III)配合物,其分子式为99mTcX(CDO)(CDOH)2B-R,其结构如通式(1)所示:
其中,X是阴离子配体,分别为F、Cl、N3或SCN;R为下述基团:
2.如项1所述的含芳基硼酸的99mTc(III)配合物,其中,所述通式 (1)中X为F、Cl,R为下述基团:
3.如项1所述的含芳基硼酸的99mTc(III)配合物,其为下述化合物,99mTc-3Sboroxime:
99mTc-4Sboroxime:
99mTc-3SPboroxime:
4.一种用于制备如项1~3中任一项所述的含芳基硼酸的99mTc(III)配合物的药盒配方,其特征在于,配方成分包含2mg的环己二酮二肟 (CDOH2)、2~5mg的R取代硼酸、50~60μg的SnX2·2H2O(优选为 50μg)、9mg的柠檬酸、2mg的二乙基三胺五乙酸(DTPA)、20~50mg的氯化钠、20~40mg的γ-环糊精。
5.如项4所述的药盒配方,其中,配方成分包含2mg的环己二酮二肟 (CDOH2)、4mg的R取代硼酸、50μg的SnX2·2H2O,9mg的柠檬酸、 2mg的二乙基三胺五乙酸(DTPA)、20mg的氯化钠、20mg的γ-环糊精。
6.如项4所述的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-3Sboroxime,所述配方中含有2mg的环己二酮二肟(CDOH2)、 2mg的3-(甲磺酰基)苯基硼酸、50μg的SnCl2·2H2O、9mg的柠檬酸、 2mg的二乙基三胺五乙酸(DTPA)、20mg的氯化钠、20mg的γ-环糊精。
7.如项4所述的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-4Sboroxime,所述配方中含有2.0mg的环己二酮二肟 (CDOH2)、4.0mg的4-(甲磺酰基)苯基硼酸、50μg的SnCl2·2H2O, 9.0mg的柠檬酸、2.0mg的二乙基三胺五乙酸(DTPA)、20.0mg的氯化钠,40.0mg的γ-环糊精。
8.如项4所述的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-3SPboroxime,所述配方中含有2.0mg的环己二酮二肟 (CDOH2)、4.0mg的3-(甲磺酰基)吡啶基硼酸、50μg的SnCl2· 2H2O,9.0mg的柠檬酸、2.0mg的二乙基三胺五乙酸(DTPA)、20.0 mg的氯化钠、40.0mg的γ-环糊精。
9.如项1~3中任一所述的含芳基硼酸的99mTc(III)配合物在制备心肌灌注显像剂中的应用。
发明的效果
本发明的配合物比现有化合物具有以下几方面的有益效果:
1、99mTcX(CDO)(CDOH)2B-R分子中的放射性锝-99m,可用于单光子发射计算机断层成像(SPECT)且价格低廉。
2、使用本发明的药盒制备99mTcX(CDO)(CDOH)2B-R,所使用的化学合成试剂均是市售商品,来源广泛,容易获得,只需简单步骤即可完成显像剂的制备,而且标记率和放射化学纯度高,因此较适合于临床应用推广。
3、本发明所述的99mTcX(CDO)(CDOH)2B-R,其具有很好的心脏初始摄取和滞留,与已报道的心肌灌注显像剂99mTc-Teboroxime相比,生物性能更佳,能适用于时间更长的临床显像方案,能适用于临床常用的SPECT 设备,因此更具临床应用价值。
附图说明
[图1]是表示99mTc-3Sboroxime的放射性HPLC谱图(RCP>95%)。
[图2]是表示99mTc-4Sboroxime的放射性HPLC谱图(RCP>95%)。
[图3]是表示9mTc-3SPboroxime的放射性HPLC谱图(RCP>95%)。
[图4]是表示99mTc-3Sboroxime,99mTc-4Sboroxime,99mTc-3SPboroxime 和已报道的99mTc-Teboroxime在各组织中的摄取值。
[图5]是表示99mTc-3Sboroxime,99mTc-4Sboroxime,99mTc-3SPboroxime 和99mTc-Teboroxime的心/背景(心/血液、心/肝、心/肺和心/肌肉)的比值。
[图6]是表示99mTc-3Sboroxime,99mTc-4Sboroxime,99mTc-3SPboroxime 和99mTc-Teboroxime在SD大鼠中注射后0-5min的SPECT/CT显像研究图。
[图7]是表示99mTc-3Sboroxime(Top)及99mTc-3SPboroxime(bottom) 在SD大鼠中分别于注射后,0-5,5-10,10-15,15-20,20- 25和25-30min的SPECT显像研究图,其中,p.i.SA=短轴;VLA =垂直长轴;HLA=水平长轴。
[图8]是表示99mTc-3Sboroxime(top)和99mTc-3SPboroxime(bottom) 在中华小型猪中的SPECT静息显像图。
具体实施方式
下面以99mTc-3Sboroxime、99mTc-4Sboroxime和99mTc-3SPboroxime为例,通过实施例详述本发明,但本发明并不限于这些实施例。考虑到X为F 或CI等时结构上的相似性以及如项1中列出的各种磺酰基结构上的相似性,本领域技术人员可预期在本发明的范围内均可取得优异的技术效果。
1、化合物的制备
材料:CDOH2(环己二酮二肟),硼酸,SnCl2·2H2O,柠檬酸,DTPA (二乙烯三胺五乙酸),γ-环糊精,3S(3-(甲磺酰基)苯基硼酸),3SP (3-(甲磺酰基)吡啶基硼酸),4S(4-(甲磺酰基)苯基硼酸)。均购买自Sigma/Aldrich。Na99mTcO4来自原子高科股份有限公司
HPLC仪器与方法:仪器:Waters 1525型二元高压液相色谱系统, 2998型全波长UV检测器,Raytest GabiStar放射性检测器。
色谱柱:SUNFIRE C18 5μm 4.6X150mm
流速:1mL/min
流动相:A:10mM醋酸铵缓冲液(pH=6.8)B:甲醇。
方法:梯度洗脱,0-5min,30%A;5-15min,30-10%
(1)[99mTcCl(CDO)(CDOH)2B-3S]的制备:
[99mTcCl(CDO)(CDOH)2B-3S]采用药盒化的方法进行制备,在含有 CDOH22mg,3S(3-(甲磺酰基)苯基硼酸)4mg,SnCl2·2H2O 50μg,柠檬酸9mg,DTPA 2mg,氯化钠20mg,γ-环糊精50mg的西林瓶中加入99mTcO4 -溶液1.0mL(370-1110MBq),于100℃反应10 min。然后,用20%的丙二醇生理盐水稀释至3.7MBq/mL。最后得到的标记物无需进一步纯化,进行HPLC检测,结果如图1所示。
路线1:99mTc-3Sboroxime的制备路线
(2)[99mTcCl(CDO)(CDOH)2B-4S]的制备:
[99mTcCl(CDO)(CDOH)2B-4S]采用药盒化的方法进行制备,在含有 CDOH22mg,4S(4-(甲磺酰基)苯基硼酸)4.5mg,SnCl2·2H2O 50μg,柠檬酸9mg,DTPA 2mg,氯化钠20mg,γ-环糊精40mg的西林瓶中加入99mTcO4 -溶液1.0mL(370-1110MBq),于100℃反应10-15 min。然后,用20%的丙二醇生理盐水稀释至3.7MBq/mL。最后得到的标记物无需进一步纯化,进行HPLC检测,结果如图2所示。.
路线2:99mTc-4Sboroxime的制备路线
路线3:99mTc-3SPboroxime的制备路线
(3)[99mTcCl(CDO)(CDOH)2B-3SP]的制备:
[99mTcCl(CDO)(CDOH)2B-3SP]采用药盒化的方法进行制备,向含有 CDOH22mg,3SP(3-(甲磺酰基)吡啶基硼酸)4.5mg,SnCl2·2H2O 50μg,柠檬酸9mg,DTPA 2mg,氯化钠20mg,γ-环糊精40mg的西林瓶中加入99mTcO4 -溶液1.0mL(370-1110MBq),于100℃反应10-15 min。然后用20%的丙二醇生理盐水稀释至3.7MBq/mL。最后得到的标记物无需进一步纯化,进行HPLC检测,结果如图3所示。
注射液的制备:
将上述包含99mTc的放射性注射液通过0.22μm的无菌滤膜,滤膜用0.5 mL含有50%丙二醇的生理盐水溶液冲洗。然后将所得滤液稀释至370- 550MBq/mL。生物分布实验中注射剂量约为1.1MBq/mL,注射体积为 0.1mL/只。显像研究中注射剂量约为370MBq/mL,注射体积为0.2- 0.5mL。
2、实验结果
(1)生物分布结果:
将8-12只雌性和8-12只雄性大鼠随机平均分成5组,每只大鼠经尾静脉注射所需示踪剂100-111KBq,然后在注射后的第2、5、 15、30和60min用戊巴比妥钠(100-200mg/kg)将大鼠麻醉处死。用 Perkin Elmer Wizard-2470-counter测量心、脑、脂肪、肠、肾、肝、肺、肉、脾、冠状动脉血管等脏器的放射性计数,最终计算其生物分布数据 (%ID/g)。
在下述表1~3中,分别示出了将99mTc-3Sboroxime、99mTc-4Sboroxime和99mTc-3SPboroxime向SD大鼠(200-220g)中注射后的第2、5、 15、30和60min的各脏器处的%ID/g值。
如上述,表1~3中示出了示踪剂[99mTcCl(CDO)(CDOH)2B-R] (R=3S,3SP and 4S)在大鼠中的生物分布数据。从上述数据可确认,在注射后第2分钟心肌摄取99mTc-3Sboroxime>99mTc- 3SPboroxime≈99mTc-4Sboroxime。在肝中的摄取99mTc-3SPboroxime<99mTc-4Sboroxime≈99mTc-3Sboroxime。另外,三者在肺中的摄取没有明显差别。令人意外的是,99mTc-3Sboroxime、99mTc-3SPboroxime 和99mTc-4Sboroxime的心/肝比值均高于已报道的示踪剂99mTc- Teboroxime。可见,如本发明通式(1)所述的R取代硼酸的引入对该类示踪剂的性能有显著影响,取得了优异的心脏初始摄取和滞留效果。99mTc-3Sboroxime和99mTc-4Sboroxime为同分异构体,二者的脂溶性相当,在其他非靶脏器的摄取类似,然而在心脏摄取却明显不同。另外,99mTc-3Sboroxime与99mTc-3SPboroxime相比,99mTc-3SPboroxime在注射后两分钟的心肌摄取明显偏低.
(2)正常组织的药代动力学研究结果
放射性示踪剂在血液、肝、肺和肌肉中高的排泄率会增加示踪剂的心/背景的比值,从而得到高质量的心肌SPECT显像图。在图4和图 5中,列出了99mTc-3Sboroxime、99mTc-3SPboroxime、99mTc- 4Sboroxime和已报道的99mTc-Teboroxime在不同组织的摄取值以及心/背景的比值。总体来讲,99mTc-3Sboroxime、99mTc-3SPboroxime、99mTc-4Sboroxime血液本底(图4:0.33-0.45%ID/g)与99mTc- Teboroxime(图4:0.49%ID/g)接近;但是由于它们具有较高的心肌摄取,从而使得心/血液的比值大于99mTc-Teboroxime。同时,99mTc-3Sboroxime、99mTc-3SPboroxime、99mTc-4Sboroxime由于具有较低的肺部和肌肉摄取,从而使得它们的心/肺、心/肌肉比值高于99mTc- Teboroxime(参见图5)。在这三个示踪剂当中,99mTc-3Sboroxime的心肌摄取最高,但是心/肝的比值与99mTc-Teboroxime类似。相比较而言,在注射后15min时,99mTc-3SPboroxime由于高的心肌初始摄取和较快的肝清除,它的心/肝的比值大于99mTc-Teboroxime。99mTc- 3Sboroxime、99mTc-3SPboroxime、99mTc-4Sboroxime在脂肪与冠状动脉血管中的摄取均比较低,分别为(约0.3%ID/g))和(0.4~ 0.6%ID/g)。由这些结果可证明:99mTc-3Sboroxime、99mTc- 3SPboroxime、99mTc-4Sboroxime作为心肌灌注显像剂要优于99mTc- Teboroxime。
(3)SD大鼠中的SPECT显像研究.
SPECT显像采用u-SPECT-II/CT进行采集。采集之前实验动物采用含有3%异氟烷的空气进行麻醉,其流量为350mL/min,开始采集之后异氟烷的比例变为2.5%,气流流速为250mL/min。示踪剂注射体积为0.5mL,活度为120-150MBq。采集方案:6帧,5min/ 帧。将上述包含99mTc的放射性注射液通过0.22μm的无菌滤膜,滤膜用0.5mL含有20%丙二醇的生理盐水溶液冲洗,所得溶液稀释至370 -550MBq/mL。生物分布实验中注射体积为0.1mL/只,显像研究中注射体积为0.2-0.5mL。显像实验结束之后,实验动物安放于专属场所监护。选取注射后0-5min作为研究时间,将99mTc- 3Sboroxime,99mTc-4Sboroxime,99mTc-3SPboroxime的显像结果与99mTc-Teboroxime进行对比。从图6的显像结果看,99mTc-3SPboroxime 由于具有较低的肝肺本底,显像质量最佳。另外,如图7所示,分别对比了99mTc-3Sboroxime和99mTc-3SPboroxime在注射后0-5,5- 10,10-15,15-20,20-25和25-30min等时间点的显像结果。由结果可见,在0-5min时的心肌摄取最高,显像质量也是最好的。99mTc-3SPboroxime由于具有较低的肝肺本底和较长的心肌滞留时间,使得即使与同一申请人之前报道的效果较佳的99mTc- PAboroxime和99mTc-5Fboroxime相比,也具有很大的优势。99mTc- 4Sboroxime与99mTc-3SPboroxime在注射后2min的心肌摄取类似,但是99mTc-4Sboroxime心肌滞留稍差些。可见,其中的99mTc- 3SPboroxime和99mTc-3Sboroxime生物性能尤为优异。
对于[99mTcX(CDO)(CDOH)2B-R]类示踪剂来说,如本发明所述的特定的R(即含磺酰基的苯基、吡啶基等类似物)取代的硼酸盐的引入对改进心肌摄取,心肌清除速率及排泄率方面非常有效。以SD大鼠为模型的生物性能评价中99mTc-3Sboroxime和99mTc-3SPboroxime初始心肌摄取高,心肌滞留稳定,心/背景的比值高,显像质量清晰,非常有潜力成为新一代的心肌灌注显像剂。其中,99mTc-3Sboroxime的心肌摄取最高,滞留时间也最长。另外,其中的99mTc-3SPboroxime由于具有更低的肝肺本底,从而使其具有较佳的显像质量。这些优异的生物性能决定本发明的[99mTcX(CDO)(CDOH)2B-R]是潜在的SPECT心肌灌注显像剂。
(4)中华小型猪的SPECT显像研究。
以23-26kg的小型猪作为模型进行SPECT/CT显像研究,雌雄各一只。实验地点在阜外医院核医学科。静息与负荷试验在一天之内完成,实验动物采用静脉注射3%戊巴比妥钠进行麻醉,给药剂量为30 mg/kg。显像仪器为SIEMENS ET-CT。静脉注射放射性示踪剂99mTc-3Sboroxime和99mTc-3SPboroxime(约300MBq),然后用2mL生理盐水冲洗注射管路。采集方案:6帧,5min/帧。静息实验完成后,经左耳静脉注射ATP,给药速度为0.16mg/min/Kg。2.5min之后经股静脉注射99mTc-3Sboroxime(约900MBq),2mL生理盐水冲洗注射管路。动态采集方案为6帧,5min/帧。
如图8所示,对于这两个示踪剂而言,最佳的显像时间段是0- 5min。相比较而言,99mTc-3Sboroxime的肝脏摄取偏高。因此,99mTc-3SPboroxime作为心肌灌注显像剂更有优势。
产业上的可利用性
由上述结果可知,本发明的含芳基硼酸的99mTc(III)配合物与目前已报道的99mTc-Teboroxime相比,在多个方面均具备明显的优势,可适用于临床。
Claims (8)
3.一种用于制备权利要求1或2所述的含芳基硼酸的99mTc(III)配合物的药盒配方,其特征在于,配方成分包含2mg的环己二酮二肟、2~5mg的R取代硼酸、50~60μg的SnX2·2H2O、9mg的柠檬酸、2mg的二乙基三胺五乙酸(DTPA)、20~50mg的氯化钠、20~40mg的γ-环糊精。
4.如权利要求3所述的药盒配方,其中,配方成分包含2mg的环己二酮二肟、4mg的R取代硼酸、50μg的SnX2·2H2O,9mg的柠檬酸、2mg的二乙基三胺五乙酸(DTPA)、20mg的氯化钠、20mg的γ-环糊精。
5.一种用于制备权利要求2所述的含芳基硼酸的99mTc(III)配合物的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-3Sboroxime,所述配方中含有2mg的环己二酮二肟、2mg的3-(甲磺酰基)苯基硼酸、50μg的SnCl2·2H2O、9mg的柠檬酸、2mg的二乙基三胺五乙酸(DTPA)、20mg的氯化钠、20mg的γ-环糊精。
6.一种用于制备权利要求2所述的含芳基硼酸的99mTc(III)配合物的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-4Sboroxime,所述配方中含有2.0mg的环己二酮二肟、4.0mg的4-(甲磺酰基)苯基硼酸、50μg的SnCl2·2H2O,9.0mg的柠檬酸、2.0mg的二乙基三胺五乙酸(DTPA)、20.0mg的氯化钠,40.0mg的γ-环糊精。
7.一种用于制备权利要求2所述的含芳基硼酸的99mTc(III)配合物的药盒配方,其中,所述含芳基硼酸的99mTc(III)配合物为99mTc-3SPboroxime,所述配方中含有2.0mg的环己二酮二肟、4.0mg的3-(甲磺酰基)吡啶基硼酸、50μg的SnCl2·2H2O、9.0mg的柠檬酸、2.0mg的二乙基三胺五乙酸(DTPA)、20.0mg的氯化钠、40.0mg的γ-环糊精。
8.权利要求1或2所述的含芳基硼酸的99mTc(III)配合物在制备心肌灌注显像剂中的应用。
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CN1054070A (zh) * | 1990-01-18 | 1991-08-28 | E.R.斯奎布父子公司 | 含生化活性基团的铼二肟和锝-99m二肟配合物的硼酸加合物 |
CN103772440A (zh) * | 2014-01-10 | 2014-05-07 | 北京师范大学 | 一种锝-99m标记的高级脂肪酸衍生物 |
CN106749416A (zh) * | 2016-11-21 | 2017-05-31 | 中国医学科学院阜外医院 | 一类含芳基硼酸的99mTc(Ⅲ)配合物及其药盒配方和应用 |
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EP0199260A2 (en) * | 1985-04-15 | 1986-10-29 | E.R. Squibb & Sons, Inc. | Boronic acid adducts of technetium-99M dioxime complexes |
CN1054070A (zh) * | 1990-01-18 | 1991-08-28 | E.R.斯奎布父子公司 | 含生化活性基团的铼二肟和锝-99m二肟配合物的硼酸加合物 |
CN103772440A (zh) * | 2014-01-10 | 2014-05-07 | 北京师范大学 | 一种锝-99m标记的高级脂肪酸衍生物 |
CN106749416A (zh) * | 2016-11-21 | 2017-05-31 | 中国医学科学院阜外医院 | 一类含芳基硼酸的99mTc(Ⅲ)配合物及其药盒配方和应用 |
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