CN111518137B - 锝-99m标记含异腈的氨基酸衍生物及制备方法和应用 - Google Patents
锝-99m标记含异腈的氨基酸衍生物及制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种结构通式为[99mTc‑(CNAA)6]+的锝‑99m标记含异腈的氨基酸衍生物及制备方法和应用。通过配体CNAA的合成以及[99mTc‑(CNAA)6]+的制备两个步骤,得到[99mTc‑(CNAA)6]+配合物。该配合物制备简便,放射化学纯度高,稳定性好,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,是一种具有推广应用价值的新型肿瘤显像剂。
Description
技术领域
本发明属于放射性药物领域,特别涉及一种锝-99m标记含异腈的氨基酸衍生物及制备方法和应用。
背景技术
氨基酸是构成蛋白质的主要成分,在人体其他生命活动中不可或缺。由于肿瘤细胞中蛋白质代谢旺盛,对氨基酸需求增加且肿瘤细胞的氨基酸转运增强,因此可以通过放射性核素标记氨基酸及其衍生物用于肿瘤显像。研究表明放射性核素标记的氨基酸及其衍生物可以克服2-18F-2-脱氧-D-葡萄糖([18F]FDG)的一些不足,如O-(2-[18F]氟代乙基)-L-酪氨酸([18F]FET)可以更好的区分肿瘤和炎症部位。由于99mTc可以通过99Mo/99mTc发生器淋洗获得,其具有优良的核性质而且99mTc标记的药物可通过药盒化制备,易于临床推广使用,因此研制新型99mTc标记的氨基酸类肿瘤显像剂具有重要的现实意义。
异腈(RNC)作为一种单齿配体可以与99mTc(I)配位形成正一价的稳定性优良的[99mTc-(CNR)6]+配合物,如99mTc-甲氧基异丁基异腈(99mTc-MIBI)是临床上现广泛应用的心肌灌注显像剂。基于以上背景,本发明以常见的氨基酸为原料,对其进行结构修饰,使其与含有异腈基团的活化酯反应以得到含异腈的氨基酸衍生物,将其进行99mTc标记来探求新型SPECT肿瘤显像剂,具有重要的科学意义和实用价值。
发明内容
本发明的目的是提供一种可用于肿瘤显像的锝-99m标记含异腈的氨基酸衍生物,同时也提供其制备方法。
为了实现上述目的,本发明提供的一种锝-99m标记含异腈的氨基酸衍生物,结构通式为[99mTc-(CNAA)6]+,其结构如式(I)所示:
该结构式中:以99mTc+核为中心核,CNAA配体分子中异腈的碳原子与99mTc(I)配位形成六配位的[99mTc-(CNAA)6]+配合物。n为大于或等于2的整数,R为H,CH3,CH(CH3)2,CH2CH(CH3)2,CH(CH3)CH2CH3,CH2COOH,CH2CONH2,(CH2)2COOH,(CH2)2CONH2,(CH2)2SCH3,CH2OH,CH(CH3)OH,CH2SH,
锝-99m标记的含异腈的氨基酸衍生物的制备方法,其制备步骤如下:
a:配体CNAA的合成:
称取适量氢氧化钠于圆底烧瓶中,加入适量甲醇溶解,然后加入适量氨基酸和化合物1,室温过夜反应。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CNAA。
具体合成路线为:
b:[99mTc-(CNAA)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸溶于生理盐水中,加入一定量的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入适量的配体CNAA和新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNAA)6]+配合物。
具体制备步骤如下:
1.CNLeuAA的合成
称取适量氢氧化钠于100mL圆底烧瓶中,加入适量甲醇溶解,然后加入L-亮氨酸和化合物1(n=5),室温过夜反应。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CNLeuAA。
2.CNMetAA的合成
称取适量氢氧化钠于100mL圆底烧瓶中,加入适量甲醇溶解,然后加入L-蛋氨酸和化合物1(n=5),室温过夜反应。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CNMetAA。
3.[99mTc-(CNLeuAA)6]+和[99mTc-(CNMetAA)6]+的制备
称取适量的柠檬酸钠、L-半胱氨酸溶于生理盐水中,加入一定量的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入适量的配体CNLeuAA和新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNLeuAA)6]+配合物。
称取适量的柠檬酸钠、L-半胱氨酸溶于生理盐水中,加入一定量的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入适量的配体CNMetAA和新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNMetAA)6]+配合物。
通过上述方法制备的[99mTc-(CNLeuAA)6]+和[99mTc-(CNMetAA)6]+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,在心、肝、肺等非靶器官中的摄取值低,是性能优良的可用于肿瘤显像的新型SPECT分子探针。
本发明[99mTc-(CNAA)6]+配合物的性能测定:
1.配合物的鉴定
[99mTc-(CNAA)6]+采用高效液相色谱(HPLC)法鉴定:用C18反向柱,SCL-10AVP型高压液相色谱仪,A相为纯水,B相为乙腈,梯度为0-2min B相为10%,2-5min B相由10%变为90%,5-20min B相为90%,20-24min B相由90%变为10%,24-25min B相为10%。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 -:2.6min;[99mTc-(CNLeuAA)6]+:9.9min;[99mTc-(CNMetAA)6]+:9.8min。
2.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-(CNAA)6]+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),重复五组,测得logP值为[99mTc-(CNLeuAA)6]+:-1.99±0.04;[99mTc-(CNMetAA)6]+:-2.93±0.07,表明其皆为亲水性物质。
3.配合物的稳定性测定
将标记物在室温下放置6小时后测定其放射化学纯度,结果表明其在室温下放置6小时后放射化学纯度仍然大于90%,说明其体外稳定性良好。
4.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标记液(约7.4×105Bq),注射1小时和2小时后断头处死小白鼠。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)。每个时项的小鼠数为5只。结果见表1。
表1[99mTc-(CNLeuAA)6]+和[99mTc-(CNMetAA)6]+在S180小鼠中的生物分布
5.配合物在荷瘤小鼠的SPECT显像
从荷S180肉瘤模型小鼠的尾静脉注射[99mTc-(CNLeuAA)6]+或[99mTc-(CNMetAA)6]+溶液(约18.5MBq),2小时后,腹腔注射戊巴比妥麻醉。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显像结果表明其在肿瘤中浓集明显,除了在肾脏中有较高浓集外在其他非靶器官中摄取较低,表明其可作为亲肿瘤性能优良的新型SPECT分子探针。
具体实施方式
下面通过实施例详述本发明:一种锝-99m标记含异腈的氨基酸衍生物,结构通式为[99mTc-(CNAA)6]+,其结构式如下:
该结构式中:以99mTc+核为中心核,CNAA配体分子中异腈的碳原子与99mTc(I)配位形成六配位的[99mTc-(CNAA)6]+配合物。n为大于或等于2的整数,R为H,CH3,CH(CH3)2,CH2CH(CH3)2,CH(CH3)CH2CH3,CH2COOH,CH2CONH2,(CH2)2COOH,(CH2)2CONH2,(CH2)2SCH3,CH2OH,CH(CH3)OH,CH2SH,
锝-99m标记的含异腈的氨基酸衍生物的制备方法,其制备步骤如下:
a:配体CNAA的合成:
称取适量氢氧化钠于圆底烧瓶中,加入适量甲醇溶解,然后加入适量氨基酸和化合物1,室温过夜反应。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CNAA。
具体合成路线为:
b:[99mTc-(CNAA)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸溶于生理盐水中,加入一定量的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入适量的配体CNAA和新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNAA)6]+配合物。
具体制备步骤如下:
1.CNLeuAA的合成
具体合成路线为:
称取氢氧化钠0.22g(5.5mmol)于100mL圆底烧瓶中,加入80mL甲醇溶解,然后加入L-亮氨酸0.66g(5.0mmol)和化合物1 1.74g(n=5,6.0mmol),室温过夜反应。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0.44g,产率32%。1H NMR(400MHz,Methanol-d4)δ7.95(s,1H),4.30(d,J=7.6Hz,1H),3.15(t,J=7.0Hz,2H),2.18(t,J=7.2Hz,2H),1.64-1.43(m,7H),1.35-1.27(m,2H),0.87(dd,J=12.0,6.1Hz,6H);13C-NMR(100MHz,Methanol-d4)δ(ppm):179.97,174.27,154.31,53.23,41.16,40.91,35.42,28.63,25.73,24.87,24.71,22.42,20.82;IR:3286.25,2954.97,2931.82,2868.17,2220.57,2149.68,1640.95,1576.82,1424.44,1167.91,941.75,728.62,564.18,419.04;HR-MS(ESI)for C13H21N2O3:found253.1560,calcd 253.1557.
2.CNMetAA的合成
具体合成路线为:
称取氢氧化钠0.22g(5.5mmol)于100mL圆底烧瓶中,加入80mL甲醇溶解,然后加入L-蛋氨酸0.75g(5.0mmol)和化合物1 1.74g(n=5,6.0mmol),室温过夜反应。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0.48g,产率33%。1H NMR(400MHz,Deuterium Oxide)δ4.19(dd,J=9.1,4.4Hz,1H),3.38(ddt,J=6.6,4.0,2.0Hz,2H),2.55-2.33(m,2H),2.27-2.15(m,2H),2.03-1.95(m,4H),1.95-1.75(m,1H),1.66-1.47(m,4H),1.39-1.28(m,2H);13C-NMR(100MHz,Deuterium Oxide)δ(ppm):178.80,176.31,150.33,54.17,41.48,35.57,31.17,29.90,27.95,25.19,24.53,14.28;IR:3277.20,3072.74,2922.28,2858.63,2148.79,1637.63,1575.91,1423.53,1350.23,1317.44,1282.72,1240.28,1180.49,686.69;HR-MS(ESI)for C12H19N2O3S:found 271.1120,calcd271.1121.
3.[99mTc-(CNLeuAA)6]+和[99mTc-(CNMetAA)6]+的制备
称取2.6mg的柠檬酸钠、1.0mg的L-半胱氨酸溶于0.5mL生理盐水中,加入0.1mg的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入0.2mg的配体CNLeuAA和0.5mL新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNLeuAA)6]+配合物。
称取2.6mg的柠檬酸钠、1.0mg的L-半胱氨酸溶于0.5mL生理盐水中,加入0.1mg的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入0.2mg的配体CNMetAA和0.5mL新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的99mTc-(CNMetAA)6]+配合物。
Claims (3)
2.如权利要求1所述99mTc标记的含异腈的氨基酸衍生物的制备方法,其工艺步骤如下:
a:配体CNAA的合成:
称取适量氢氧化钠于圆底烧瓶中,加入适量甲醇溶解,然后加入适量氨基酸和化合物1,室温过夜反应,反应结束后减压蒸馏除去溶剂,柱层析纯化,其中:二氯甲烷与甲醇的比例为5:1,得到配体CNAA;
具体合成路线为:
b:[99mTc-(CNAA)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸溶于生理盐水中,加入一定量的SnCl2·2H2O,调节溶液pH为5.8-6.0,向其中依次加入适量的配体CNAA和新鲜淋洗的Na99mTcO4,沸水浴加热30min即可得到所述的[99mTc-(CNAA)6]+配合物。
3.如权利要求1所述99mTc标记的含异腈的氨基酸衍生物在制备肿瘤显像药物中的应用。
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