68Ga-NOTA-ANCP-PSMA的制备与初步评价
Preparation and Preliminary Evaluation of 68Ga-NOTA-ANCP-PSMA
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摘要: 前列腺特异性膜抗原（prostate specific membrane antigen, PSMA）作为理想靶点，68Ga标记的PSMA小分子抑制剂可用于前列腺癌诊断、分期和疗效评价。为研发一种新型、具有较好理化性能的68Ga标记的PSMA小分子化合物，以1-萘基丙氨酸、4-胺甲基环己甲酸和苯丙氨酸组成的链式氨基酸为侧链，设计了新型的PSMA小分子抑制剂68Ga-NOTA-ANCP-PSMA，并对其标记方法和体外理化性质进行了研究。采用固相合成法制备前体化合物，经确证结构后，进行68Ga标记。分别对温度、pH、前体化合物投入量等标记条件进行了实验，并测定了放射性标记物的稳定性和脂水分配系数。标记条件为pH=3.0～4.5、90.0～95.0 ℃、前体化合物质量浓度不低于20 mg/L，在优化的标记条件下，标记率可达95%以上。纯化后的标记物在磷酸缓冲液体系下和小牛血清蛋白体系下2 h的体外稳定性较好。脂水分配系数为-1.36±0.01(n=3)，与PSMA-617相比，该化合物的亲脂性稍高。标记化合物的体内分布显示：血液清除较快，以肾脏代谢为主，在非靶器官摄取较低。Abstract: Prostate specific membrane antigen(PSMA) as a specific target antigen for prostate cancer has become an ideal target. The use of PSMA labeled with 68Ga has become a hot topic in prostate cancer diagnosis, staging and efficacy evaluation. To develop a new 68Ga labeled PSMA compound with better physical and chemical properties, a novel PSMA small molecule inhibitor 68Ga-NOTA-ANCP-PSMA was designed, with 1-naphthylalanine, tranexamic acid and phenylalanine as the side chain. And its labeling method, physical and chemical properties and preliminary evaluation were carried out. 68Ga was labeled to the PSMA compound directly, and the labeling conditions such as temperature, pH and precursor compound input amount were tested, respectively. The stability and octanol-water partition coefficient were determined, and the in vitro distribution of normal mice was determined. The labeling conditions should be controlled at pH=3.0-4.5, the labeling temperature was selected at 90.0-95.0 ℃, and the precursor compound concentration was not lower than 20 mg/L. In optimal labeling conditions, the labeling yield achieves to over 95%. The purified labeled compound shows good vitro stability, and radiochemical purity is stable in the PBS system and the serum protein system for 2 hours. The octanol-water partition coefficient is -1.36±0.01(n=3), which is a little higher than PSMA-617. The distribution in normal mice show that the compound clears fast in blood, mainly by kidney metabolism, lower uptake shows in non-target organs. The compound shows good properties, which is expected to be used for the diagnosis of prostate for PET, and provide a basis for developing prostate cancer theranostic targeted molecules probe for the future.
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Keywords:
- prostate cancer /
- 68Ga /
- PSMA
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