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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557076/
• 关键词: Radioiodine; Radioipharmaceuticals; Internal radiation therapy; Metabolic activity; Melanoma; Melanin biosynthesis; Kinetics regulation; Serum protein binding; 放射性ヨウ素標識薬剤; メラニン形成; ヨウ素標識アミノ酸

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新的放射性碘标记的放射性药物，用于肿瘤的检测和治疗，它对肿瘤的特征代谢具有亲和力。3-碘-4-羟基苯基-L-半胱氨酸（I-L-PC）与酪氨酸酶（酪氨酸酶是黑色素生物合成的限速酶）有相互作用。本研究以酪氨酸酶为靶点，合成了3-碘-4-羟基苯基半胱胺（I-PCA），并研究了其在荷黑色素瘤小鼠体内的生物分布。在不加载体的条件下，采用传统的氯胺-T法制备了I-PCA。I-PCA在荷B16黑色素瘤的C57 BL 6小鼠体内的生物分布显示出快速的血液清除、肾脏排泄和在正常组织中的低蓄积。结果表明，I-PCA实现了对黑色素形成的期望亲和力。不 ...更多信息 I-PCA在恶性黑色素瘤的诊断中具有很高的潜力。此外，I-PCA在正常组织中的蓄积量低，清除快，用I-131标记后可作为治疗用放射性药物。I-IMP是一种脑血流促进剂，约70%与血清蛋白结合。如果能用具有高蛋白结合亲和力的置换剂抑制放射性药物与血清蛋白的结合，则可提高该示踪剂的总清除率和组织分布。评价I-IMP与几种结合置换剂之间的相互作用以改善脑成像。用临床上可用的HSA位点II置换剂6 MNA使I-IMP的游离分数率增加至对照的1.2倍。在猴脑血管造影研究中，脑内蓄积显著加速。事实上，6 MNA处理增加了猴血清中的游离I-IMP。由于置换法易于应用于人体研究，因此竞争置换法在临床应用中可以控制放射性药物的组织分布和动力学。少

项目成果

Akizawa H., Arano Y: "Novel methods of altering pharmacokinetics in radiopharmaceutical design : metabolizable linkers and pharmacokinetics"Q. J. Nucl. Med.. 46. 206-223 (2002)

Akizawa H.、Arano Y：“放射性药物设计中改变药代动力学的新方法：可代谢连接体和药代动力学”Q。

Nishii R., Kawai K., Nagamachi S., Arano Y., et al.: "A Novel Radiopharmaceutical for Detection of Malignant Melanoma Based on Melanin Formation : 3-Iodo-4-hydroxyphenyl-Lーcystein"Nucl. Med. Commun.. 24. 575-582 (2003)

Nishii R.、Kawai K.、Nagamachi S.、Arano Y. 等人：“一种基于黑色素形成检测恶性黑色素瘤的新型放射性药物：3-碘-4-羟基苯基-半胱氨酸”Nucl Med。 . 24. 575-582 (2003)

Uehara T., Fujioka Y., Saji H., Arano Y.: "Approaches to Reduce Renal Radioactivity Levels of Antibody Fragments."Biomed. Res. Trace Elements. 12. 152-158 (2001)

Uehara T.、Fujioka Y.、Saji H.、Arano Y.：“降低抗体片段肾脏放射性水平的方法”。Biomed。

Kawai K. Takamura H., Nishii R., Jinnouchi S., Nagamachi S., Tamura S., Arimori K., Otagiri M.: "Competitive Displacement of Serum Protein Binding to Regulate Pharmacokinetics."In Serum Albumin and α_1-Acid Glycoprotein from Basic Sciences to Clinical App

Kawai K. Takamura H.、Nishii R.、Jinnouchi S.、Nagamachi S.、Tamura S.、Arimori K.、Otagiri M.：“血清蛋白结合的竞争性置换以调节药代动力学。”血清白蛋白和 α_1-酸糖蛋白从基础科学到临床应用

Akizawa H., Arano Y., Mifune M., Iwado A., Saito Y., Mukai T., Uehara, T., Ono M., Fujioka Y., Ogawa K., Kiso Y., Saji H.: "Effect of Molecular Charges on Renal Uptake of ^<111>In-DTPA-conjugated Peptides."Nucl. Med. Biol.. 28. 761-768 (2001)

秋泽 H.、荒野 Y.、三船 M.、岩户 A.、齐藤 Y.、向井 T.、上原 T.、小野 M.、藤冈 Y.、小川 K.、木曾 Y.、佐治 H.：“