摘要
本研究开发了一种可与白蛋白结合并在前列腺癌中具有高摄取和滞留的新型^(177)Lu标记放射性药物分子[^(177)Lu]Lu-DOTA-CPN-PSMA,以1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸(DOTA)为双功能螯合剂,谷氨酸-脲-赖氨酸(Glu-Urea-Lys)为靶向基团,在小分子抑制剂的连接部位引入白蛋白结合基团4-(对-甲苯基)丁酸(CP)和喹啉环。利用固相合成法合成前体小分子化合物DOTA-CPN-PSMA;采用无载体的^(177)Lu核素进行标记,分别考察反应pH、反应时间、反应温度、投料比等因素对放射化学纯度的影响,确定最佳标记条件;测定标记物的脂水分配系数和体外稳定性;采用22RV1荷瘤小鼠为模型动物进行初步的SPECT/CT显像,并以[^(177)Lu]Lu-PSMA-I&T为对照进行了相关结果的对比。结果表明,在加入稳定剂龙胆酸的情况下,^(177)Lu/PSMA(mCi/μg,1 Ci=3.7×10^(10)Bq)投料比为1∶1~2∶1、反应pH值为3.5~5.5、反应温度为60~94℃、反应时间为5~15 min时,标记物放射化学纯度≥95%,最高可达99%,标记物无需进行进一步纯化;标记物在生理盐水和小牛血清中于37℃放置24 h后放射化学纯度≥95%,体外稳定性良好;脂水分配系数为-2.02,与[^(177)Lu]Lu-PSMA-I&T相比更为亲脂。初步的SPECT/CT研究表明,引入白蛋白结合基团后的[^(177)Lu]Lu-DOTA-CPN-PSMA在前列腺癌中的摄取高于[^(177)Lu]Lu-PSMA-I&T且滞留时间长,72 h后在肿瘤中仍有较高摄取,与此同时,在肾脏中的摄取低于[^(177)Lu]Lu-PSMA-I&T。初步研究结果表明,该标记物值得作为治疗前列腺癌的候选放射性药物开展进一步研究。
A novel PSMA targeting molecule[^(177)Lu]Lu-DOTA-CPN-PSMA with high uptake and long retention in prostate cancer was developed,in which DOTA was used as the bifunctional chelator,glutamic acid-urea-lysine(Glu-Urea-Lys)was used as the targeting group,and 4-(p-tolyl)butyric acid(CP)group together with quinoline ring were introduced at the linker of this molecule.The precursor DOTA-CPN-PSMA was synthesized using solid-phase peptide synthesis method.DOTA-CPN-PSMA was labeled with carrier-free^(177)Lu.The influences of pH,reaction time,temperature,and ratio of^(177)Lu/PSMA on the radiolabeling were investigated respectively,and the optimal labeling condition was determined accordingly.The lipid water partition coefficient and in vitro stability of[^(177)Lu]Lu-DOTA-CPN-PSMA were also measured.Preliminary SPECT/CT imaging study of[^(177)Lu]Lu-DOTA-CPN-PSMA was performed in nude mice bearing 22RV1 tumor and compared with[^(177)Lu]Lu-PSMA-I&T.The optimization of the labeling condition shows that the addition of gentisic acid is essential,and the reaction pH is at the range of 3.5-5.5,the reaction temperature and time is 60-94℃and 5-15 min respectively,the ratio of^(177)Lu/PSMA(mCi/μg,1 Ci=3.7×10^(10) Bq)is controlled at 1∶1-2∶1.The radiochemical purity reaches over 95%,and even up to 99%.The results of in vitro stability study show that the radiochemical purity is remained≥95%after being incubated in saline and bovine serum at 37℃for 24 h.So that the solution of[^(177)Lu]Lu-DOTA-CPN-PSMA is used for imaging study directly without further purification.The lipid-water partition coefficient of[^(177)Lu]Lu-DOTA-CPN-PSMA is-2.02,indicate that it is more lipophilic than[^(177)Lu]Lu-PSMA-I&T.Preliminary SPECT/CT studies reveal that[^(177)Lu]Lu-DOTA-CPN-PSMA is mainly metabolized through kidneys.Compared with images of[^(177)Lu]Lu-PSMA-I&T,higher uptake in prostate tumors and lower uptake in the kidneys are displayed.After 72 h,[^(177)Lu]Lu-DOTA-CPN-PSMA demonstrates longer retension in tumor than[^(177)Lu]-PSMA-I&T,b
作者
罗田伟
孙明月
张文辉
高菲
王宁
黄旭虎
陈欢
李洪玉
LUO Tian-wei;SUN Ming-yue;ZHANG Wen-hui;GAO Fei;WANG Ning;HUANG Xu-hu;CHEN Huan;LI Hong-yu(HTA Co.,Ltd.,Beijing 102413,China;China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Engineering and Industrialization of Radiopharmaceuticals,Beijing 102413,China;China National Nuclear Corporation Engineering Research Center of Radiopharmaceuticals,Beijing 102413,China)
出处
《核化学与放射化学》
CAS
CSCD
北大核心
2023年第6期573-582,I0005,共11页
Journal of Nuclear and Radiochemistry
基金
中核集团青年英才计划资助项目。
