CN112175025B - 一种含苯环的葡萄糖衍生物及其应用 - Google Patents
一种含苯环的葡萄糖衍生物及其应用 Download PDFInfo
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Abstract
本发明涉及放射性药物化学和临床核医学技术领域,具体涉及一种含苯环的葡萄糖衍生物及其应用。所述含苯环的葡萄糖衍生物具有如通式(I)所示的结构,将其用放射性核素标记得到的放射性制剂,在肿瘤中具有高摄取,同时肿瘤/非靶比值好,是一种有推广应用价值的新型肿瘤放射性药物。
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,具体涉及一种含苯环的葡萄糖衍生物及其应用。
背景技术
癌症严重威胁着人类健康,对癌症的早发现、早治疗对于提高生存率、降低死亡率、减少患者病痛、节省治疗费用等具有重要意义。核医学显像技术能够在分子层面对肿瘤进行诊断,且具有灵敏度高、特异性好、无创等优点,已经成为肿瘤早期诊断的一大类检测手段,特别是随着正电子发射断层扫描术(PET)和单光子发射断层扫描术(SPECT)与CT等的融合使用,放射性核素肿瘤显像已经成为核医学诊断的优势之一。
葡萄糖是细胞代谢的主要能量物质,而恶性肿瘤细胞快速增殖,代谢活跃,对葡萄糖的需求远高于正常细胞。基于这一特性,结合核医学显像,可以将葡萄糖类衍生物用放射性核素进行标记以用于肿瘤显像。18F-氟代脱氧葡萄糖(18F-FDG)是目前临床应用最广的肿瘤显像剂,但18F需要加速器制备且诊断费用较为昂贵,一定程度上限制了其在临床上的推广应用。相对于PET,SPECT仪器数量更多,诊断费用更加低廉,且随着碲锌镉(CZT)晶体在SPECT中的应用,以及图像重建技术的发展,SPECT的分辨率和灵敏度也在不断提高。因此,研制一种制备简便且价格低廉的新型SPECT肿瘤显像剂具有重要的现实意义。99mTc是临床上使用最为广泛的SPECT核素,其具有适宜的半衰期(T1/2=6.02h),发射140keV的γ单光子且99Mo-99mTc发生器的推广应用使得99mTc放射性药物成为临床应用最多的SPECT药物。
申请号为201710451094.8,公开号为CN107245087A的发明专利申请,公开了一种99mTc标记含异腈的葡萄糖衍生物及制备方法和应用,发现在99mTc标记的葡萄糖衍生物的研究中,99mTc标记的含异腈的葡萄糖衍生物99mTc-(CN5DG)6 +有较好的靶/非靶比值,但其肿瘤摄取值还有待提高。
申请号为202010032704.2,公开号为CN111138504A的发明专利申请,公开了一种99mTc-CNPEDG配合物及其制备方法和应用,其在螯合基团(异氰基)和靶向基团(D-葡糖胺)之间引入了一个苯环,成功制备了99mTc-CNPEDG配合物,制备方法简单,99mTc-CNPEDG在肿瘤中有较高的摄取和良好的滞留,但其在血液中的清除较慢,同时肿瘤摄取和靶/非靶比值仍有待进一步提高。
发明内容
针对现有技术的不足,本发明提供了一种含苯环的葡萄糖衍生物及其应用,该葡萄糖衍生物稳定性好,制备简便,进行放射性标记后用于肿瘤诊疗,肿瘤摄取高且靶/非靶比值好,在肿瘤诊疗领域具有重要的科学意义和应用前景。
具体地,本发明提供以下技术方案:
一种含苯环的葡萄糖衍生物,所述含苯环的葡萄糖衍生物的结构式为(I):
式中:
R2表示氢、氘、卤素、CN、NO2、C1-12烷基、C2-12烯基或C2-12炔基;
n表示0或0以上的整数;
当m=0,n=1,R3表示氢时,由R1表示的取代基不在苯环的4位上。
优选的,上述含苯环的葡萄糖衍生物中,由R1表示的取代基在苯环的3位或4位上,所述R1中,R3表示氢、氘、卤素、C1-7烷基、C2-7烯基或C2-7炔基,m表示0或1;
R2表示氢、氘、卤素、C1-7烷基、C2-7烯基或C2-7炔基;
n表示0、1或2。
优选的,上述含苯环的葡萄糖衍生物中,m和n的和表示2或2以上的整数。
优选的,上述含苯环的葡萄糖衍生物中,由R1表示的取代基在苯环的3位上。本发明发现与由对位R1取代基制备得到的99mTc配合物相比,由间位的R1取代基制备得到的99mTc配合物在非靶器官中有更低的摄取,有更高的肿瘤/血,肿瘤/肌肉,肿瘤/肺比值,能够针对肿瘤诊疗取得更好的效果。
最优选的,所述含苯环的葡萄糖衍生物的结构式为下面任意一种:
本发明还提供一种放射性制剂,所述放射性制剂包含用放射性核素标记的上述含苯环的葡萄糖衍生物。
优选的,上述放射性制剂中,所述放射性核素部分包括金属放射性核素或非金属放射性核素。
优选的,上述放射性制剂中,所述金属放射性核素为99mTc、99Tc、94mTc、94Tc、52Mn、186Re或188Re,所述非金属放射性核素为18F、75Br、76Br、77Br、82Br、120I、123I、124I、125I或131I。
最优选的,上述放射性制剂中,所述放射性核素为99mTc,所述放射性制剂的结构式为(II):
式中:
本发明还提供上述放射性制剂在肿瘤诊断领域和/或肿瘤治疗领域中的应用。
本发明的有益效果在于:本发明提供一种含苯环的葡萄糖衍生物,将其用放射性核素标记得到的放射性制剂,在肿瘤中具有高摄取,同时肿瘤/非靶比值好,是一种有推广应用价值的新型肿瘤放射性药物。
具体实施方式
本发明提供了一种含苯环的葡萄糖衍生物及其应用,在一种优选的实施方式中,本发明提供结构通式为99mTc-CNBDG的放射性制剂:
式中:
由R1表示的取代基在苯环的3位或4位上;
n表示0、1或2;
当m=0,n=1时,由R1表示的取代基不在苯环的4位上。
其制备步骤如下:
(1)配体的合成
称取适量D-葡糖胺盐酸盐和NaOH于25mL圆底烧瓶中,加入无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入化合物1的甲醇溶液,滴加完毕后继续在室温下反应24h,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CNBDG。
具体合成路线为:
所述化合物1的结构式为:
(2)99mTc-CNBDG的制备
将1mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.06mgSnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入0.5mg配体CNBDG和1-2mL新鲜淋洗的Na99mTcO4,100℃下反应20min即可得到99mTc-CNBDG配合物。
通过上述方法制备的99mTc-CNBDG配合物的放射化学纯度大于90%,体内外稳定性良好,其在荷瘤小鼠肿瘤部位有较高的摄取和良好的滞留,靶/非靶比值好。与现有技术公开的99mTc-CNPEDG和99mTc-(CN5DG)6 +相比,99mTc-CNBDG的肿瘤/肌肉、肿瘤/血液比值更高,达到了提高该类显像剂靶/非靶比值的发明目的,利于作为新型肿瘤显像剂推广应用。
以下实施例用于说明本发明,但不用来限制本发明的范围。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。
本发明中,所用仪器等未注明生产厂商者,均为可通过正规渠道商购买得到的常规产品。所述方法如无特别说明均为常规方法,所述原材料如无特别说明均能从公开商业途径而得。
实施例1
本实施例提供一种99mTc标记的含苯环的葡萄糖衍生物,简称为99mTc-4-CNPeDG,结构式如下:
其制备步骤如下:
1、4-CNPeDG的合成:
称取0.269g D-葡糖胺盐酸盐和0.055g氢氧化钠于25mL圆底烧瓶中,加入20mL无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入10mL含有0.337g 4-(2-异氰基乙基)苯甲酸-2,3,5,6-四氟苯基酯的甲醇溶液,之后继续在室温下反应24h。反应结束后减压蒸馏除去溶剂,残留固体经过硅胶柱层析(二氯甲烷:甲醇=5:1)分离纯化,干燥后得到浅黄色固体0.13g,产率37%。
1H NMR(400MHz,methanol-d4):δ7.83(dd,J=15.8,8.5Hz,2H),7.37(dd,J=22.4,8.2Hz,2H),5.25(t,J=3.0Hz,1H),4.07(dt,J=10.7,3.1Hz,1H),3.97-3.80(m,3H),3.80-3.67(m,2H),3.46(dt,J=21.3,8.3Hz,2H),3.03(t,J=6.6Hz,2H)。
HRMS(m/z):found 335.1252(calc.335.1248 for C16H19N2O6[M-H]-)。
IR(KBr)/cm-1:2146.86(-N≡C)。
2、99mTc-4-CNPeDG的合成:
将1mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.06mgSnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入0.5mg 4-CNPeDG和1-2mL新鲜淋洗的Na99mTcO4,100℃下反应20min即得到本实施例所述的99mTc-4-CNPeDG。
实施例2
本实施例提供一种99mTc标记的含苯环的葡萄糖衍生物,简称为99mTc-4-CNMBDG,结构式如下:
其制备步骤如下:
1、4-CNMBDG的合成:
称取0.220g D-葡糖胺盐酸盐和0.045g氢氧化钠于25mL圆底烧瓶中,加入10mL无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入10mL含有0.290g 4-异氰基甲基苯乙酸-2,3,5,6-四氟苯基酯的甲醇溶液,之后继续在室温下反应24h。反应结束后减压蒸馏除去溶剂,残留固体经过硅胶柱层析(二氯甲烷:甲醇=5:1)分离纯化,干燥后得到浅黄色固体0.150g,产率50%。
1H-NMR(400MHz,D2O):δ7.42(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),5.18(d,J=3.7Hz,1H),3.98-3.82(m,3H),3.81-3.74(m,2H),3.74-3.63(m,3H),3.60-3.37(m,2H)。
HRMS(m/z):found 337.1398(calc.337.1394 for C16H21N2O6[M+H]+)。
IR(KBr)/cm-1:2152.65(-N≡C)。
2、99mTc-4-CNMBDG的合成:
将1mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.06mgSnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入0.5mg 4-CNMBDG和1-2mL新鲜淋洗的Na99mTcO4,100℃下反应20min即得到本实施例所述的99mTc-4-CNMBDG。
实施例3
本实施例提供一种99mTc标记的含苯环的葡萄糖衍生物,简称为99mTc-3-CNBzDG,结构式如下:
其制备步骤如下:
1、3-CNBzDG的合成:
称取0.326g D-葡糖胺盐酸盐和0.066g氢氧化钠于25mL圆底烧瓶中,加入10mL无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入10mL含有0.499g 3-异氰基苯甲酸-2,3,5,6-四氟苯基酯的甲醇溶液,之后继续在室温下反应24h。反应结束后减压蒸馏除去溶剂,残留固体经过硅胶柱层析(二氯甲烷:甲醇=5:1)分离纯化,干燥后得到浅黄色固体0.128g,产率29%。
1H-NMR(400MHz,D2O):δ7.97-7.79(m,2H),7.66(dd,J=17.2,8.0Hz,1H),7.56(dtd,J=27.2,7.8,2.2Hz,1H),5.34(d,J=3.2Hz,1H),4.13(dd,J=10.7,3.4Hz,1H),4.03-3.89(m,2H),3.89-3.74(m,1H),3.62-3.44(m,2H)。
HRMS(m/z):found 307.0939(calc.307.0935for C14H15N2O6[M-H]-)。
IR(KBr)/cm-1:2127.58(-N≡C)。
2、99mTc-3-CNBzDG的合成:
将1mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.06mgSnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入0.5mg 3-CNBzDG和1-2mL新鲜淋洗的Na99mTcO4,100℃下反应20min即得到本实施例所述的99mTc-3-CNBzDG。
实施例4
本实施例提供一种99mTc标记的含苯环的葡萄糖衍生物,简称为99mTc-3-CNPEDG,结构式如下:
其制备步骤如下:
1、3-CNPEDG的合成:
称取0.220g D-葡糖胺盐酸盐和0.044g氢氧化钠于25mL圆底烧瓶中,加入15mL无水甲醇,室温下搅拌至固体完全溶解,然后向其中加入10mL含有0.312g 3-异氰基甲基苯甲酸-2,3,5,6-四氟苯基酯的甲醇溶液,之后继续在室温下反应24h。反应结束后减压蒸馏除去溶剂,残留固体经过硅胶柱层析(二氯甲烷:甲醇=5:1)分离纯化,干燥后得到浅黄色固体0.119g,产率37%。
1H NMR(400MHz,methanol-d4):δ7.96-7.78(m,2H),7.66-7.44(m,2H),5.26(d,J=3.2Hz,1H),4.84(s,2H),4.08(dd,J=10.7,3.4Hz,1H),3.99-3.79(m,3H),3.74(dd,J=11.9,5.5Hz,1H),3.41(dt,J=30.3,8.5Hz,1H)。
HRMS(m/z):found 323.1241(calc.323.1237 for C15H19N2O6[M+H]+)。
IR(KBr)/cm-1:2156.51(-N≡C)。
2、99mTc-3-CNPEDG的合成:
将1mg柠檬酸钠、1mg L-半胱氨酸溶于适量生理盐水中,向其中加入0.06mgSnCl2·2H2O,调节溶液pH为6.0,然后依次向其中加入0.5mg 3-CNPEDG和1-2mL新鲜淋洗的Na99mTcO4,100℃下反应20min即得到本实施例所述的99mTc-3-CNPEDG。
对比例1
对比例1按照专利CN111138504A中具体实施方式的技术方法制备99mTc-CNPEDG,其结构式为:
对比例2
对比例2按照专利CN107245087A中具体实施方式的技术方法制备99mTc-(CN5DG)6 +,其结构式为:
试验例
1、实施例1-4提供的放射性制剂的层析鉴定
(1)TLC法
采用薄层色谱层析法(TLC)进行标记物放射化学产率和放射化学纯度的测定,所用展开体系为聚酰胺薄膜-醋酸铵(1M)/甲醇(体积比:2/1),该体系下,各放射性组分的Rf值如表1所示。
表1放射性组分在聚酰胺薄膜-醋酸铵(1M)/甲醇体系下的Rf值
由上述层析鉴定所测得的99mTc-CNBDG配合物的放射化学产率和放射化学纯度均大于90%,未经进一步纯化即用于后续实验。
(2)HPLC法
采用高效液相色谱(HPLC)进行标记物放射化学纯度的鉴定:SHIMADZU高效液相色谱仪(CL-20AVP),Kromasil C18反相柱(5μm,250×4.6mm),Gabi raytest放射性检测器。淋洗梯度如表2所示,流速为1mL/min,A相为含0.1%三氟乙酸的纯水,B相为含0.1%三氟乙酸的乙腈。
表2配合物的梯度洗脱条件
HPLC鉴定结果表明,实施例1-4提供的放射性制剂的保留时间分别为:99mTc-4-CNPeDG:10.7min;99mTc-4-CNMBDG:10.6min;99mTc-3-CNBzDG:10.4min;99mTc-3-CNPEDG:10.6min。
2、脂水分配系数的测定
取标记液100μL(10μCi)置于2mL的离心管里,然后向其中加入950μL正辛醇和850μL PBS(0.025M,pH 7.4),涡旋3min(2500rpm),静置待溶液分层后于离心机中离心5min(9000rpm),从两相中各取出3份100μL,于γ-counter中分别测定其放射性计数。脂水分配系数P=有机相放射性计数/水相放射性计数,通常以log P作为脂水分配系数的表示。经测定实施例1-4提供的放射性制剂的log P值如表3所示,所有log P值均为负数,说明它们都是水溶性物质。
表3配合物99mTc-CNBDG的脂水分配系数
3、稳定性测定
(1)体外稳定性测定
将实施例1-4提供的放射性制剂分别在室温下生理盐水中和在37℃下小鼠血清中放置4小时后通过HPLC测定其放射化学纯度,实验结果表明实施例1-4提供的放射性制剂在室温下生理盐水中和在37℃下小鼠血清中放置4小时后放射化学纯度均大于90%,说明其具有良好的体外稳定性。
(2)体内稳定性测定
将含实施例1-4的放射性制剂的标记液(0.1-0.2mL,74MBq)通过尾静脉注射到小鼠体内,1h后断头处死,收集尿液和血液,通过HPLC测定其放射化学纯度,结果表明99mTc-CNBDG配合物在给药1h后在尿液和血液中的放射化学纯度仍大于90%,说明其具有良好的体内稳定性。
4、荷瘤小鼠体内生物分布测定
将含实施例1-4的放射性制剂的标记液(0.1mL,370kBq)通过尾静脉注入荷S180肿瘤的小鼠体内,记下注射时间后在不同的时间点(30min,120min)将小鼠断颈处死(每个时相5只小鼠),解剖后取出心、肝、肺、肾、脾、骨、肌肉、小肠、血液和肿瘤等感兴趣组织或器官,用γ-counter分别测定各脏器的放射性计数,并通过各脏器的质量换算后得到各个脏器的摄取值(以%ID/g为单位),标记物在荷瘤小鼠体内的生物分布结果见表4-表7。
表4 99mTc-4-CNPeDG在荷S180肿瘤小鼠体内生物分布结果(n=5,mean±SD,%ID/g)
表5 99mTc-4-CNMBDG在荷S180肿瘤小鼠体内生物分布结果(n=5,mean±SD,%ID/g)
表6 99mTc-3-CNBzDG在荷S180肿瘤小鼠体内生物分布结果(n=5,mean±SD,%ID/g)
表7 99mTc-3-CNPEDG在荷S180肿瘤小鼠体内生物分布结果(n=5,mean±SD,%ID/g)
从结果可以看出,实施例1-4提供的放射性制剂在肿瘤中滞留好,而在非靶器官中快速代谢,给药120min后,肿瘤/肌肉和肿瘤/血液比值较高。
将实施例1-4提供的放射性制剂与对比例1的99mTc-CNPEDG、对比例2的99mTc-(CN5DG)6 +在荷瘤小鼠体内生物分布数据做比较,结果见表8。
表8实施例1-4提供的放射性制剂与99mTc-CNPEDG、
99mTc-(CN5DG)6 +配合物在荷S180肿瘤小鼠体内的生物分布结果对比(120minp.i.,%ID/g,mean±SD)
以上结果表明,实施例1-4提供的放射性制剂的肿瘤摄取和靶/非靶比值均高于99mTc-(CN5DG)6 +,尽管99mTc-4-CNPeDG、99mTc-3-CNBzDG、99mTc-3-CNPEDG的肿瘤摄取低于99mTc-CNPEDG,但它们在非靶器官中的摄取更低、清除更快,使得靶/非靶比值显著增加。值得一提的是,99mTc-4-CNMBDG具有更高的肿瘤摄取,且在血液中的清除更快,从而大大提高了肿瘤/血液比值。
此外,研究过程中发现,由间位R1取代基制备的99mTc配合物(如99mTc-3-CNBzDG、99mTc-3-CNPEDG)相较于由对位R1取代基制备的99mTc配合物(如99mTc-4-CNBzDG、99mTc-4-CNPEDG)具有更高的肿瘤/肌肉、肿瘤/血液和肿瘤/肺比值(见表9)。
表9 99mTc-3-CNPEDG与99mTc-4-CNPEDG、99mTc-3-CNBzDG与99mTc-4-CNBzDG的靶/非靶比值对比(120min p.i.,mean±SD)
附:所述99mTc-4-CNPEDG与99mTc-3-CNPEDG的不同点、所述99mTc-4-CNBzDG与99mTc-3-CNBzDG的不同点均仅在于R1取代基位点。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (5)
2.根据权利要求1所述的含苯环的葡萄糖衍生物,其特征在于,m和n的和表示2。
3.根据权利要求1所述的含苯环的葡萄糖衍生物,其特征在于,由R1表示的取代基在苯环的3位上。
5.权利要求4所述的放射性制剂在肿瘤诊断领域和/或肿瘤治疗领域制备肿瘤显像剂中的应用。
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