CN113200960A - 锝-99m标记含异腈的PEG链修饰的FAPI衍生物及制备方法和应用 - Google Patents
锝-99m标记含异腈的PEG链修饰的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‑PEG‑FAPI)6]+的锝‑99m标记含异腈的PEG链修饰的FAPI衍生物及制备方法和应用。通过配体CN‑PEG‑FAPI的合成以及[99mTc‑(CN‑PEG‑FAPI)6]+的制备两个步骤，得到[99mTc‑(CN‑PEG‑FAPI)6]+配合物。该配合物制备简便，放射化学纯度高，稳定性好，在荷瘤小鼠体内的非靶脏器摄取较低，肿瘤部位有很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PEG链修饰的FAPI衍生物及制备方法和应用。
背景技术
成纤维细胞激活蛋白(FAP)是近年来肿瘤诊疗中重要的靶点，通过放射性核素标记成纤维细胞激活蛋白抑制剂(FAPI)及其衍生物用作肿瘤放射性药物成为当前研究热点。我们课题组在2020年研制出一种锝-99m标记含异腈的FAPI衍生物(专利申请号：202011382815.2)，但是该药物在肿瘤中的摄取值偏低且在肝、肾等非靶器官摄取偏高，因此性能更加优良的99m Tc标记的FAPI肿瘤显像剂值得开发。
聚乙二醇(PEG)是中性、无毒且具有独特理化性质和良好的生物相溶性的高分子聚合物，也是经美国食品药品监督管理局(FDA)批准的极少数能作为体内注射药用的合成聚合物之一。PEG具有高度的亲水性，在水溶液中有较大的水动力学体积，当偶联到药物分子或药物表面时，可以将其优良性质赋予修饰后的药物分子，改变它们在水溶液中的生物分配行为和溶解性，在其修饰的药物周围产生空间屏障，减少药物的酶解。相关研究表明(Z.Liu,G.Niu,J.Shi,S.Liu,et al.Eur.J.Nucl.Med.Mol.Imag.2009,36,947-957；L.Wang,J.Shi,Y.-S.Kim,et al.Mol.Pharm.2009,6,231-245)，在配体中引入PEG链将增加配合物在肿瘤中的摄取和靶与非靶比值，提高药物在体内的药代动力学性质。基于以上背景，本发明以FAPI原料，对其进行结构修饰，使其与含有异腈的PEG链修饰的活化酯反应以得到含异腈的PEG链修饰的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PEG链修饰的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PEG链修饰的FAPI衍生物，结构通式为[99mTc-(CN-PEG-FAPI)6]+，其结构如式(I)所示：
该结构式中：以99mTc+核为中心核，CN-PEG-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-PEG-FAPI)6]+配合物。n为大于0的整数。
锝-99m标记的含异腈的PEG链修饰的FAPI衍生物的制备方法，其制备步骤如下：
a:配体CN-PEG-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＝5:1)得到配体CN-PEG-FAPI。
具体合成路线为：
b:[99mTc-(CN-PEG-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-PEG-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-PEG-FAPI)6]+配合物。
通过上述方法制备的[99mTc-(CN-PEG-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，非靶脏器摄取低，注射FAPI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-PEG-FAPI)6]+配合物的性能测定：
1.配合物的鉴定
[99mTc-(CN-PEG-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％，2-5minB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-PEG-FAPI)6]+保留时间(Rt)为：11.05min。
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-PEG-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-PEG-FAPI)6]+：-2.38±0.07，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-PEG-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U87肿瘤Balb/c模型小鼠的尾静脉注射0.10mL标记液(约3.7×105Bq)，注射后1h和4h时断头处死小鼠。此外，使用FAPI对配合物[99mTc-(CN-PEG-FAPI)6]+进行小鼠体内抑制实验，方法如下：将100μL含有50μg FAPI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3.7×105Bq)，1h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3只。结果见表1。
表1[99mTc-(CN-PEG-FAPI)6]+在荷U87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U87肿瘤Balb/c模型小鼠的尾静脉注射[99mTc-(CN-PEG-FAPI)6]+溶液0.1mL(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50μg FAPI的生理盐水溶液，然后注射配合物0.1mL(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PEG链修饰的FAPI衍生物，结构通式为[99mTc-(CN-PEG-FAPI)6]+，其结构式如下：
该结构式中：以99mTc+核为中心核，CN-PEG-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-PEG-FAPI)6]+配合物。n为大于0的整数。
锝-99m标记的含异腈的PEG链修饰的FAPI衍生物的制备方法，其制备步骤如下：
a:配体CN-PEG-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-PEG-FAPI。
具体合成路线为：
b:[99mTc-(CN-PEG-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-PEG-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-PEG-FAPI)6]+配合物。
具体制备步骤如下：
1.CN-PEG-FAPI的合成
具体合成路线为：
称取30mg(0.06mmol)FAPI于圆底烧瓶中，加入1mL DMF溶解，然后加入0.08mL(0.60mmol)三乙胺和34mg(0.08mmol)化合物1(n＝4)，室温反应5h。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-PEG-FAPI 20mg，产率44％。1H NMR(400MHz,Methanol-d4)δ8.74(dd,J＝4.5,1.5Hz,1H),8.04–7.91(m,2H),7.55(dd,J＝4.5,1.5Hz,1H),7.45(dt,J＝9.5,1.9Hz,1H),5.20–5.05(m,1H),4.33–4.09(m,6H),3.68–3.57(m,20H),3.08–2.87(m,10H),2.73–2.63(m,2H),2.23(h,J＝5.9,5.3Hz,2H)；13C NMR(101MHz,Methanol-d4)δ171.17,169.27,168.30,157.83,146.96,144.04,141.58，129.67,125.99,123.47,119.14,117.15,104.26,70.09,69.89,69.81,69.77,68.50,66.74,65.94,54.49,52.39,52.01,44.57,43.90,41.65,41.34,39.81,32.82,24.71；IR(KBr)/cm-1:3412.22,2935.78,2739.04,2675.38,2492.14,2152.65,1682.00,1658.85,1541.19,1471.75,1435.10,1379.16,1311.65,1232.57,1199.77,1172.77,1128.41,1112.97,1031.96；HR-MS(ESI)for C36H48N7O8F2[M+H]+:found 744.3527,calcd 744.3526.
2.[99mTc-(CN-PEG-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-PEG-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-PEG-FAPI)6]+配合物。
Claims (3)
1.一种99mTc标记的含异腈的PEG链修饰的FAPI衍生物，结构通式为[99mTc-(CN-PEG-FAPI)6]+，其结构如下式所示：
该结构式中：以99mTc+核为中心核，CN-PEG-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-PEG-FAPI)6]+配合物。n为大于0的整数。
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-PEG-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-PEG-FAPI；
具体合成路线为：
b:[99mTc-(CN-PEG-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-PEG-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-PEG-FAPI)6]+配合物。
3.如权利要求1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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