CN106075484A - 核素标记的前列腺特异性膜抗原靶向抑制剂及其制备方法 - Google Patents
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Abstract
本发明提供新型核素标记的前列腺特异性膜抗原靶向抑制剂,其为放射性核素标记的DKFZ‑PSMA‑617,所述放射性核素包括64Cu、68Ga、89Zr中的至少一种。本发明还提供核素标记DKFZ‑PSMA‑617的制备方法。本发明的核素标记DKFZ‑PSMA‑617性质稳定,显像效果好,对PSMA有高的亲和力和功能活性,有利于早期前列腺癌的诊断与准确分期,并为乳腺癌、胃腺癌的诊断提供新思路,经进一步临床前动物水平研究证实,其有望成为具有良好应用前景的靶向PSMA显像剂及肿瘤治疗剂。
Description
技术领域
本发明涉及核医学领域,具体地说,涉及一种核素标记的前列腺特异性膜抗原靶向抑制剂及其制备方法。
背景技术
随着核医学与分子生物学的深入发展与融合,医学影像技术迈向分子影像学时代,其中正电子发射计算机断层显像(Positron Emission Tomography,PET)进行功能学显像使得人们真正从分子水平开始认识并诊断疾病,尤其在肿瘤的诊疗方面凸显出其优势。通过示踪病变组织的受体变化、细胞信号转导的异常,从而克服现代诊断技术中的缺陷,为肿瘤的早期诊断、临床分期、疗效评估提供依据,并对预后进行评价,同时也可应用于肿瘤的靶向治疗。
目前分子核医学中代谢显像在临床中应用最广泛,其中最多见的为18F-FDG,但因其为非特异性显像剂,在前列腺癌诊断方面存在很多不足,因此亟需研发特异性受体对前列腺癌进行显像,以真正发挥PET显像的优势。当然无论肿瘤的靶向显像还是治疗,都依托于放射性药物的研制与合成。若肿瘤中某种受体高水平表达,则可利用受体与配体高特异性、高亲和性结合的特点,将配体进行放射性核素标记,从而作为示踪剂与受体高密度表达部位相结合从而对肿瘤部位显像。
PSMA(Prostate Specific Membrane Antigen,PSMA)作为特异性的靶点最初被7E-11所识别并定义,其在前列腺癌细胞中高度表达,尽管唾液腺、小肠等正常组织中也有一定程度的表达,但表达水平仅为癌细胞的1/100-1/1000,且PSMA表达水平随肿瘤的分级与分期的升高而升高;之后研究发现PSMA虽在正常血管中并无表达,但普遍高表达于实体肿瘤的新生血管内皮细胞中,胃腺癌、大肠癌中表达分别高达66.4%和84.2%,经免疫组化证实74.0%原发性乳腺癌、100%的乳腺癌脑转移病灶的新生血管中呈PSMA表达阳性,且表达PSMA新生血管所占比例与患者的十年生存率成正相关,这将有望拓宽PSMA作为潜在诊断与治疗靶点的应用范围。
PSMA为Ⅱ型跨膜糖蛋白,含750个氨基酸,膜内段含19个氨基酸,膜外段为707个氨基酸,跨膜段含24个氨基酸,膜内段与膜外段均含有抗原表位。DKFZ-PSMA-617则是与膜外段抗原位点结合,M等通过竞争性结合实验已证实其与PSMA的高亲和力,动物水平实验发现LNCaP异种移植瘤肿瘤摄取可被2-PMPA所阻滞(8.47±4.09%ID/g;0.98±0.32%ID/g 2-PMPA共注射),证实其结合的高特异性。此外,DKFZ-PSMA-617还可有效内化并滞留在细胞内,利于进行示踪性显像,而且药代动力学特性较好,肿瘤显像清晰,24h时T/B=1058,T/M=529,优于近年来开发并经临床证实显像效果优良的示踪剂PSMA-11。
发明内容
本发明的目的是提供一种核素标记的前列腺特异性膜抗原靶向抑制剂及其制备方法。
本发明基于以下构思:DKFZ-PSMA-617含DOTA双功能螯合剂,考虑到铜为人体微量金属元素,64Cu同位素具有合适的半衰期,良好的核素性能,因此对DKFZ-PSMA-617进行64Cu标记。64Cu的半衰期为12.7h,使得显像时间可适当延长,有利于显示肿瘤更多的生理和生化特性,而且不会对患者造成不必要的放射性损伤。能量为0.656MeV,占17.4%分支比的β+粒子适用于PET显像;另外,64Cu发射β-粒子占39%,又有作为治疗性药物的潜力,因此64Cu核素标记物有诊治一体化的功能,不仅可以用于肿瘤的定位而且可消除术后残余病灶,减少术后常规放化疗对病人造成的损伤,还能够在一定程度上提高患者的生活质量。
为了实现本发明目的,本发明提供的核素标记的前列腺特异性膜抗原靶向抑制剂,其为放射性核素标记的DKFZ-PSMA-617,所述放射性核素包括64Cu、68Ga、89Zr等中的至少一种。其中,DKFZ-PSMA-617含双功能螯合剂DOTA(1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸),进行放射性核素标记得到相应的放射性分子探针能够与PSMA结合,从而通过核医学手段准确定位PSMA高表达的肿瘤组织,达到疾病靶向分子影像诊断、治疗的目的。
本发明还提供靶向PSMA的肿瘤显像剂和治疗药物,其含有所述核素标记的前列腺特异性膜抗原靶向抑制剂。
本发明还提供所述核素标记的前列腺特异性膜抗原靶向抑制剂在制备靶向PSMA的肿瘤显像剂和治疗药物中的应用。
本发明还提供所述核素标记的前列腺特异性膜抗原靶向抑制剂在制备PET/CT分子诊断显像剂中的应用。
本发明进一步提供所述核素标记的前列腺特异性膜抗原靶向抑制剂的制备方法,向10~20μg DKFZ-PSMA-617中依次加入0.1~1.0mL pH4.5-5.5的0.1M NaAC和92.5MBq50-120MBq的64CuCl2或89Zr4+淋洗液,80~110℃反应10~20min,即得目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
优选地,向10μg DKFZ-PSMA-617中依次加入0.2mL pH4.5-5.5的0.1M NaAC和92.5MBq的64CuCl2或89Zr4+淋洗液,95℃反应15min,即得目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
当标记率小于90%时,用Sep-pak C18Column分离纯化所述目标化合物,使目标化合物的放射性化学纯度大于99%。使用前,Sep-pak柱需用无水乙醇和高纯水活化,并用生理盐水洗脱放射性杂质,然后再用80%乙醇洗脱出目标化合物。
64Cu-PSMA-617的体外稳定性分析结果显示,其在0.9%NaCl溶液中24h内均能保持良好的稳定性,Radio-HPLC检测其放化纯度保持在92%以上。
64Cu-PSMA-617的PET显像结果表明,64Cu-PSMA-617能够准确定位PSMA阳性肿瘤,对PSMA有高度特异性靶向性,在BGC-823荷胃腺癌裸鼠肿瘤部位的摄取较明显,PSMA高表达的唾液腺富集也随时间的延长不断增高。研究结果表明64Cu核素性质稳定,显像效果优于68Ga等正电子核素。64Cu-PSMA-617可用于正电子核医学显像,并用于PSMA高表达的前列腺癌的定位诊断与治疗,还可以实现对有大量新生血管生成以至PSMA高表达的神经胶质瘤、乳腺癌、胃腺癌等实体瘤的定位诊断与治疗。
本发明提供的新型核素标记的前列腺特异性膜抗原靶向抑制剂,性质稳定,显像效果好,对PSMA有高的亲和力和功能活性,有利于早期前列腺癌的诊断与准确分期,并为乳腺癌、胃腺癌的诊断提供新思路,经进一步临床前动物水平研究证实,其有望成为具有良好应用前景的靶向PSMA显像剂及肿瘤治疗剂。
附图说明
图1为本发明实施例1中64Cu-PSMA-617标记化合物分离纯化后的HPLC测定结果。
图2为本发明实施例2中64Cu-PSMA-617标记化合物的体外稳定性分析结果。
图3为本发明实施例3中64Cu-PSMA-617标记化合物在动物体内的PET显像结果;A、B和C分别为注射64Cu-PSMA-617后30min、8h和24h显像,灰色箭头所示方向为肿瘤,白色箭头所示方向为唾液腺。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段,所用原料均为市售商品。
本发明中涉及的DKFZ-PSMA-617购自ABX,Radeberg,德国(产品编号:9933.0001)。
实施例1新型核素64Cu、89Zr标记的DKFZ-PSMA-617的制备
向10μg DKFZ-PSMA-617中依次加入0.2mL pH4.5-5.5的0.1M NaAC和92.5MBq的64CuCl2或89Zr4+淋洗液,95℃反应15min,即得目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
当标记率小于90%时,用Sep-pak C18Column分离纯化所述目标化合物,使目标化合物的放射性化学纯度大于99%。
使用前Sep-pak柱需用5mL无水乙醇和5mL高纯水活化,并用3mL生理盐水洗脱出放射性杂质,然后再用0.8mL 80%乙醇洗脱出目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
用Radio-HPLC测定标记率及放射化学纯度。分析条件:YMC-Pack ODS-A column,1.0mL/min;0.1%TFA Water(A),0.1%TFA Acetontrile(C);0-10min(C):15%-60%。结果显示64Cu-PSMA-617标记率大于92%,放化纯度大于99%。结果见图1。
实施例2 64Cu-PSMA-617标记化合物的体外稳定性分析
取20μL(1.3MBq)分离样品64Cu-PSMA-617加入到1mL NaCl缓冲溶液中,于30℃孵育,在5min、30min、1h、2h和28h时分别取出25μL、30μL、40μL、55μL、99μL溶液进行Radio-HPLC检测。结果见图2,该结果表明化合物64Cu-PSMA-617的稳定性好。
实施例3 64Cu-PSMA-617标记化合物在动物体内的PET显像试验
取右上肢腋下种植人胃腺癌BGC-823细胞的BALB/c裸鼠(十周龄),肿瘤直径1.0-2.0cm,通过尾静脉注射18.5MBq的64Cu-PSMA-617标记化合物0.2mL,分别于注射后30min、8h和24h进行PET显像。显像前将裸鼠在Summit AS-1-000-7小动物麻醉系统中用混有3%(体积分数)异氟烷的氧气麻醉,显像过程中维持含1%(体积分数)异氟烷的氧气麻醉,显像时间为15min。结果见图3。
另外,对化合物89Zr-PSMA-617进行检测分析结果表明,其与化合物64Cu-PSMA-617的体外稳定性及显像效果近似。
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 (8)
1.核素标记的前列腺特异性膜抗原靶向抑制剂,其特征在于,其为放射性核素标记的DKFZ-PSMA-617,所述放射性核素包括64Cu、68Ga、89Zr中的至少一种。
2.靶向PSMA的肿瘤显像剂和治疗药物,其含有权利要求1所述核素标记的前列腺特异性膜抗原靶向抑制剂。
3.权利要求1所述核素标记的前列腺特异性膜抗原靶向抑制剂在制备靶向PSMA的肿瘤显像剂和治疗药物中的应用。
4.权利要求1所述核素标记的前列腺特异性膜抗原靶向抑制剂在制备PET/CT分子诊断显像剂中的应用。
5.权利要求1所述核素标记的前列腺特异性膜抗原靶向抑制剂的制备方法,其特征在于,向10~20μg DKFZ-PSMA-617中依次加入0.1~1.0mL pH4.5-5.5的0.1M NaAC和50-120MBq的64CuCl2或89Zr4+淋洗液,80~110℃反应10~20min,即得目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
6.根据权利要求5所述的方法,其特征在于,向10μg DKFZ-PSMA-617中依次加入0.2mLpH4.5-5.5的0.1M NaAC和92.5MBq的64CuCl2或89Zr4+淋洗液,95℃反应15min,即得目标化合物64Cu-PSMA-617或89Zr-PSMA-617。
7.根据权利要求5或6所述的方法,其特征在于,当标记率小于90%时,用Sep-pak C18Column分离纯化所述目标化合物,使目标化合物的放射性化学纯度大于99%。
8.根据权利要求7所述的方法,其特征在于,使用前Sep-pak柱需用无水乙醇和高纯水活化,并用生理盐水洗脱放射性杂质,然后再用80%乙醇洗脱出目标化合物。
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