DEVELOPEMENT OF RADIOIODINATED RADIOPHARMACEUTICALS FOR INTERNAL RADIATION THERAPY OF TUMOR BASED ON ITS SPECIFIC METABOLIC ACTIVITY

基于肿瘤特异性代谢活性的用于肿瘤内放射治疗的放射性碘化放射性药物的开发

基本信息

批准号：
12557076
负责人：
KAWAI Keiichi
金额：
$ 4.35万
依托单位：
Kanazawa University (2001-2002)宮崎医科大学 (2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

The aim of this study is to develop a new radiopharmaceutical labeled with radioiodine for detection and therapy of tumors, which has affinity to a characteristic metabolism in tumor. 3-Iodo-4-hydroxyphenyl-L-cysteine (I-L-PC), as we have reported previously, was found to have an interaction for tyrosinase, an essential and rate-limiting enzyme to melanin biosynthesis. In this study, considering higher affinity for tyrosinase, we synthesized 3-iodo-4-hydroxyphenylcysteamine (I-PCA) that was an amine derivative of I-L-PC and examined biodistribution study in melanoma-bearing mice.4-Hydroxyphenylcysteamine (4-PCA) was synthesized and radioiodinated in our laboratory. I-PCA was prepared by conventional chloramine-T method under no-carrier added condition. The biodistribution of I-PCA in B16 melanoma-bearing C57BL6 mice showed rapid blood clearance, renal excretion and low accumulation in normal tissue. The results suggested that I-PCA achieved the desired affinity for melanin formation. T … More hat is, I-PCA has high potentiality for diagnosis of malignant melanoma. Moreover, because I-PCA accumulated low in normal tissue and showed rapid clearance, it might be applied as a therapeutic radiopharmaceutical when labeled with I-131.Approximately 70 % of I-IMP, a cerebral blood flow agent, is bound to serum protein. If the binding of radiopharmaceutical to serum protein can be inhibited by displacers with high protein binding affinity, the total clearance and tissue distribution of this tracer would be enhanced. The interaction between I-IMP and several binding displacers was evaluated to improve cerebral imaging. The free fraction rate of I-IMP was increased up to 1.2 times of control with 6MNA, a clinically available HSA site II displacer. In monkey scintigraphic study, cerebral accumulation was significantly accelerated. Indeed, 6MNA treatment increased free I-IMP in monkey serum. Since the displacement method could easily be applied to human study, the competitive displacement can control tissue distribution and kinetics of radiopharmaceuticals in clinical application. Less

本研究的目的是开发一种用于肿瘤检测和治疗的放射性碘标记的新型放射性药物，该药物与肿瘤中的特征代谢具有亲和力，3-碘-4-羟苯基-L-半胱氨酸（I-L-PC），正如我们之前报道的，发现与酪氨酸酶有相互作用，酪氨酸酶是黑色素生物合成的必需限速酶。在这项研究中，考虑到酪氨酸酶具有较高的亲和力，我们合成了酪氨酸酶。 3-碘-4-羟基苯基半胱胺（I-PCA）是I-L-PC的胺衍生物，并在患有黑色素瘤的小鼠中进行了生物分布研究。4-羟基苯基半胱胺（4-PCA）是在我们实验室合成并放射性碘化的。采用常规氯胺-T法在不添加载体的条件下制备I-PCA在B16黑色素瘤中的生物分布。 C57BL6 小鼠表现出快速的血液清除、肾排泄和正常组织中的低积累，结果表明 I-PCA 实现了对黑色素形成的理想亲和力，因此，I-PCA 具有诊断恶性黑色素瘤的高度潜力。由于 I-PCA 在正常组织中蓄积量较低且清除速度快，因此用 I-131 标记后可用作治疗性放射性药物。大约 70% 的 I-IMP（脑血）如果放射性药物与血清蛋白的结合可以被具有高蛋白结合亲和力的置换剂抑制，则该示踪剂的总清除率和组织分布将增强 I-IMP 与几种结合之间的相互作用。评估置换剂可改善脑成像，使用 6MNA（一种临床可用的 HSA 位点 II 置换剂），I-IMP 的游离分数率增加至 1.2 倍。事实上，6MNA 处理增加了猴血清中的游离 I-IMP，由于置换方法很容易应用于人体研究，因此在临床应用中竞争性置换可以控制放射性药物的组织分布和动力学。