CN112409414A - 锝-99m标记含异腈的FAPI衍生物及制备方法和应用 - Google Patents
锝-99m标记含异腈的FAPI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‑(CN‑FAPI)6]+的锝‑99m标记含异腈的FAPI衍生物及制备方法和应用。通过配体CN‑FAPI的合成以及[99mTc‑(CN‑FAPI)6]+的制备两个步骤,得到[99mTc‑(CN‑FAPI)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,且在肿瘤中的摄取具有特异性,是一种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FAPI衍生物及制备方法和应用。
背景技术
肿瘤微环境在肿瘤的发生、发展过程中发挥着极其重要的作用。肿瘤相关成纤维细胞是构成肿瘤微环境的重要组成部分,具有极强的增殖、迁移、分泌与合成能力,在肿瘤细胞的增殖、迁移、免疫逃逸、放化疗抵抗和能量代谢中扮演着重要的角色。成纤维细胞激活蛋白(FAP)是肿瘤相关成纤维细胞表面重要的分子标志物,因其选择性地表达于大多数实体瘤基质的成纤维细胞的细胞膜上,又具有促进肿瘤细胞的增殖、细胞外基质的降解重建、肿瘤脉管系统的建立及介导肿瘤免疫抑制等功能,成为了肿瘤检测和治疗潜在的靶点。因此可以通过放射性核素标记成纤维细胞激活蛋白抑制剂(FAPI)及其衍生物用于肿瘤显像。
目前,一种68Ga标记的FAPI显像剂[68Ga]Ga-FAPI-04得到广泛的关注,临床前研究表明其具有较高的肿瘤-非靶组织比和快速的清除,但是其由于68Ga半衰期较短(68min),在一定程度上限制其临床应用。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FAPI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FAPI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FAPI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FAPI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FAPI衍生物,结构通式为[99mTc-(CN-FAPI)6]+,其结构如式(I)所示:
该结构式中:以99mTc+核为中心核,CN-FAPI配体分子中异腈的碳原子与99mTc(I)配位形成六配位的[99mTc-(CN-FAPI)6]+配合物。n为大于或等于2的整数。
锝-99m标记的含异腈的FAPI衍生物的制备方法,其制备步骤如下:
a:配体CN-FAPI的合成:
称取适量FAPI于圆底烧瓶中,加入适量DMF溶解,然后加入适量三乙胺和化合物1,室温反应。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CN-FAPI。
具体合成路线为:
b:[99mTc-(CN-FAPI)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸、甘露醇和一定量的SnCl2·2H2O溶于生理盐水中,调节溶液pH为6.0,向其中依次加入适量的配体CN-FAPI、Tween-80和新鲜淋洗的Na99mTcO4,沸水浴加热20min即可得到所述的[99mTc-(CN-FAPI)6]+配合物。
具体制备步骤如下:
1.CN-FAPI的合成
称取适量FAPI于圆底烧瓶中,加入适量DMF溶解,然后加入适量三乙胺和化合物1(n=5),室温反应。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CN-FAPI。
2.[99mTc-(CN-FAPI)6]+的制备
称取适量的柠檬酸钠、L-半胱氨酸、甘露醇和一定量的SnCl2·2H2O溶于生理盐水中,调节溶液pH为6.0,向其中依次加入适量的配体CN-FAPI、Tween-80和新鲜淋洗的Na99mTcO4,沸水浴加热20min即可得到所述的[99mTc-(CN-FAPI)6]+配合物。
通过上述方法制备的[99mTc-(CN-FAPI)6]+配合物的放射化学纯度大于95%,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,注射FAPI配体进行抑制后,肿瘤摄取显著性降低,表明其在肿瘤中的摄取具有特异性。显像结果也表明其在肿瘤部位有明显浓集,且在肿瘤中的摄取可以被FAPI配体进行抑制,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-(CN-FAPI)6]+配合物的性能测定:
1.配合物的鉴定
[99mTc-(CN-FAPI)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相为水(含0.1%三氟乙酸),B相为乙腈(含0.1%三氟乙酸),梯度为0-2min B相为10%,2-5min B相由10%变为40%,5-10min B相由40%变为90%,10-24min B相为90%,24-25min B相由90%变为10%。进样量为20μL,流速为1mL/min。测定[99mTc-(CN-FAPI)6]+保留时间(Rt)为:11.59min。
2.配合物的脂水分配系数的测定
取0.9mL pH 7.4的磷酸盐缓冲液(0.025mol/L)于5mL离心试管中,在离心试管中加入1mL正辛醇和0.1mL[99mTc-(CN-FAPI)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-(CN-FAPI)6]+:-0.86±0.03,表明其为亲水性物质。
3.配合物的稳定性测定
将配合物分别在室温下放置和37℃小鼠血清中放置4小时后测定其放射化学纯度,结果表明[99mTc-(CN-FAPI)6]+配合物在室温下和37℃小鼠血清中放置4小时后放射化学纯度大于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HT-1080肿瘤Balb/c模型小鼠的尾静脉注射0.10mL标记液(约7.4×105Bq),注射后1h和4h时断头处死小鼠。此外,使用配体CN-FAPI对配合物[99mTc-(CN-FAPI)6]+进行小鼠体内抑制实验,方法如下:将100μL含有40μg CN-FAPI配体的生理盐水溶液尾静脉注射小鼠体内,30min后注射0.10mL标记液(约7.4×105Bq),4h后断头处死小白鼠。取其心、肝、肺、肾、脾、骨、小肠、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4只。结果见表1。
表1[99mTc-(CN-FAPI)6]+在荷HT-1080肿瘤Balb/c裸鼠的生物分布
5.配合物在荷瘤小鼠的SPECT显像
从荷HT-1080肿瘤Balb/c模型小鼠的尾静脉注射[99mTc-(CN-FAPI)6]+溶液0.2mL(约18.5MBq),4小时后,腹腔注射戊巴比妥麻醉。抑制组需要提前30分钟注射100μL含有40μg CN-FAPI配体的生理盐水溶液,然后注射配合物0.2mL(约18.5MBq),4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。SPECT显像结果表明其在肿瘤中浓集明显,抑制组在肿瘤中的摄取明显降低,进一步说明该配合物在肿瘤中的摄取具有特异性,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FAPI衍生物,结构通式为[99mTc-(CN-FAPI)6]+,其结构式如下:
该结构式中:以99mTc+核为中心核,CN-FAPI配体分子中异腈的碳原子与99mTc(I)配位形成六配位的[99mTc-(CN-FAPI)6]+配合物。n为大于或等于2的整数。
锝-99m标记的含异腈的FAPI衍生物的制备方法,其制备步骤如下:
a:配体CN-FAPI的合成:
称取适量FAPI于圆底烧瓶中,加入适量DMF溶解,然后加入适量三乙胺和化合物1,室温反应。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CN-FAPI。
具体合成路线为:
b:[99mTc-(CN-FAPI)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸、甘露醇和一定量的SnCl2·2H2O溶于生理盐水中,调节溶液pH为6.0,向其中依次加入适量的配体CN-FAPI、Tween-80和新鲜淋洗的Na99mTcO4,沸水浴加热20min即可得到所述的[99mTc-(CN-FAPI)6]+配合物。
具体制备步骤如下:
1.CN-FAPI的合成
具体合成路线为:
称取50mg(0.10mmol)FAPI于圆底烧瓶中,加入1mL DMF溶解,然后加入0.139mL(1.00mmol)三乙胺和38mg(0.13mmol)化合物1(n=5),室温反应4h。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CN-FAPI 30mg,产率49%。1H NMR(400MHz,Methanol-d4)δ8.77(d,J=4.5Hz,1H),8.05(d,J=2.7Hz,1H),8.00(d,J=2.5Hz,1H),7.59(d,J=4.5Hz,1H),7.50(dd,J=9.2,2.7Hz,1H),6.75(tt,J=10.5,7.2Hz,1H),5.16(dd,J=9.4,3.1Hz,1H),4.39(t,J=6.0Hz,3H),4.31(d,J=2.0Hz,2H),4.28–4.07(m,3H),3.45(dt,J=16.5,7.6Hz,4H),2.99–2.74(m,4H),2.50–2.33(m,6H),1.71–1.35(m,8H);13C NMR(100MHz,DMSO-d6)δ170.87,168.53,168.08,159.72,157.59,147.91,144.62,141.21,131.22,125.96,123.13,119.72,118.24,114.80,105.00,66.81,54.80,53.67,53.09,45.44,44.72,41.90,41.64,41.53,32.50,28.81,26.44,26.08,24.43;HR-MS(ESI)for C31H38F2N7O4[M+H]+:found 610.2947,calcd 610.2947.
2.[99mTc-(CN-FAPI)6]+配合物的制备:
称取2.6mg柠檬酸钠、1.0mg L-半胱氨酸、10mg甘露醇和0.1mg SnCl2·2H2O溶于0.5mL生理盐水中,调节溶液pH为6.0,向其中依次加入5μg配体CN-FAPI、20mg Tween-80和0.5mL新鲜淋洗的Na99mTcO4(约370MBq),沸水浴加热20min即可得到所述的[99mTc-(CN-FAPI)6]+配合物。
Claims (3)
2.如权利要求1所述化合物的制备方法,其工艺步骤如下:
a:配体CN-FAPI的合成:
称取适量FAPI于圆底烧瓶中,加入适量DMF溶解,然后加入适量三乙胺和化合物1,室温反应。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CN-FAPI;
具体合成路线为:
b:[99mTc-(CN-FAPI)6]+配合物的制备:
称取适量的柠檬酸钠、L-半胱氨酸、甘露醇和一定量的SnCl2·2H2O溶于生理盐水中,调节溶液pH为6.0,向其中依次加入适量的配体CN-FAPI、Tween-80和新鲜淋洗的Na99mTcO4,沸水浴加热20min即可得到所述的[99mTc-(CN-FAPI)6]+配合物。
3.如权利要求1或2所述的化合物,其特征在于:所述配合物作为肿瘤显像药物在核医学领域的应用。
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