DEVELOPMENT OF RADIOIODINATED RADIOPHARMACEUTICALS FOR FUNCTION DIAGNOSIS OF CEREBRAL NEURON AND THEIR MOLECULAR DESIGN.

用于脑神经元功能诊断的放射性碘化放射性药物的开发及其分子设计。

• 批准号: 11470193
• 负责人: KAWAI Keiichi
• 金额: $ 4.42万
• 依托单位: Kanazawa University (2001)宮崎医科大学 (1999-2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470193/
• 关键词: Cerebral neuronal function; Radioipharmaceuticals; 6-Iodo-L-mem-tyrosine; Radioiodinated amino acids; Amino acid transport system; Aromatic amino acid decarboxylase; Serum protein binding; Competitive displacement; 脳機能診断薬; 放射性ヨウ素標識; 血漿蛋白結合; 結合置

L-meta-Tyrosine (L-mTyr), a precursor of catecholamines such as dopamine and nor epinephrine, is in the L-form and it has a hydroxy group at 3-position as a minimum structure of L-DOPA therefore it could probably be used as a probe for the cerebral dopaminergic presynaptic function. L-mTyr separated from D, L-racemate by chiral HPLC, was labeled with non-carrier mediated 1-125. I-125-L-mTyr had a higher accumulation in the brain and the pancreas. Its accumulation in the brain is stereo specific and energy dependent. It was resistant to deiodination, had no retention mechanism and rapidly excreted.The direct radio iodination of L-mTyr produced two geometric isomers. 6-[I-125] iodo- and 4-[I-125] iodo-L-meta tyrosine (6-I-L-mTyr, 4-I-L-mTyr) were separated by reverse phase HPLC. In the biodistribution study, 6-I-L-mTyr had a tendency to be retained in the brain. Its accumulation in the brain was energy dependent. In the blood, 6-I-L-mTyr had higher activity but was also rapidly eliminate … More d. There were also high metabolic stability and rapid clearance through renal excretion. With in vitro accumulation in tissue slices, only the accumulation of 6-I-L-mTyr was inhibited by NSD-1015. It shows that 6-I-L-mTyr had an affinity to cerebral aromatic amino acid decarboxylase (AADC), the final enzyme of dopamine biosynthesis. These findings were also confirmed by in vivo inhibition study using auto radiography. Thus, it was shown that 6-I-L-mTyr is a new radio pharmaceutical that can be both useful in assessing cerebral amino acid transport mechanism and in quantifying metabolically active AADC.Approximately 70 % of I-123-IMP, a cerebral blood flow agent, is bound to serum protein. If the binding of radio pharmaceutical 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-123-IMP and several binding displacers was evaluated to improve cerebral imaging. The serum protein binding was evaluated by ultra filtration. The free fraction rate of I-123-IMP was increased up to 1.2 times of control with 6MNA, a clinically available HAS site II displacer. The rat biodistribution showed more rapid clearance of I-123-IMP with 6MNA loading. In monkey scintigraphic study, cerebral accumulation was significantly accelerated. Indeed, 6MNA treatment increased free I-123 IMP in monkey serum study. Since the displacement method could easily be applied to human study, the competitive displacement of I-123-IMP can control their tissue distribution and kinetics in clinical application. Less

L-间-酪氨酸（L-mTyr）是多巴胺和去甲肾上腺素等儿茶酚胺的前体，具有L-型结构，3-位羟基是左旋多巴的最小结构，因此可能用作脑多巴胺能突触前功能的探针。通过手性HPLC从D，L-外消旋体分离的L-mTyr用非载体介导的1-125标记。I-125-L-mTyr在脑和胰腺中的蓄积较高。它在大脑中的积累是立体特异性和能量依赖性的。间酪氨酸具有抗脱碘、无滞留机制、排泄迅速等特点，直接放射性碘化可生成两种几何异构体。通过反相HPLC分离6-[I-125]碘-和4-[I-125]碘-L-Meta酪氨酸（6-I-L-mTyr、4-I-L-mTyr）。在生物分布研究中，6-I-L-mTyr有保留在脑中的趋势。它在大脑中的积累依赖于能量。在血液中，6-I-L-mTyr具有较高的活性，但也被迅速消除 ...更多信息 D.此外，还具有较高的代谢稳定性和通过肾脏排泄的快速清除率。在组织切片中的体外蓄积中，NSD-1015仅抑制6-I-L-mTyr的蓄积。结果表明，6-I-L-mTyr对多巴胺生物合成的最终酶脑芳香族氨基酸脱羧酶（AADC）具有亲和力。这些发现也通过使用自动射线照相术的体内抑制研究得到证实。因此，表明6-I-L-mTyr是一种既可用于评估脑氨基酸转运机制又可用于定量代谢活性AADC的新型放射性药物。如果能用高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。评价了I-123-IMP与几种结合置换剂之间的相互作用，以改善脑成像。通过超滤评价血清蛋白结合。用临床上可用的HAS位点II置换剂6 MNA使I-123-IMP的游离分数率增加至对照的1.2倍。大鼠生物分布显示，6 MNA负荷的I-123-IMP清除更快。在猴闪烁扫描研究中，脑内积聚显着加速。事实上，在猴血清研究中，6 MNA处理增加了游离I-123 IMP。由于置换法易于应用于人体研究，因此I-123-IMP的竞争置换可以控制其在临床应用中的组织分布和动力学。少

项目成果

Kawai K., et al.: "Regulation of ^<123>I-IMP cerebral accumulation by competitive displacement of serum protein binding"Journal of Labelled Compounds and Radiopharmaceuticals. 44. 462-464 (2001)

Kawai K.等人：“通过血清蛋白结合的竞争性置换调节123 I-IMP脑积聚”标记化合物和放射性药物杂志。

Leo G.Flores II,Keiichi Kawai,et al.: "Evaluation cylic acid.of DOPA decarboxylase activity in presynaptic dopaminergic neuron with 6-radioiodinated L-meta-tyrosine."Jouranl of Labelled Compounds and Radiopharmaceuticals. 42. 420-422 (1999)

Leo G.Flores II、Keiichi Kawai 等人：“用 6-放射性碘标记的 L-间位酪氨酸评估突触前多巴胺能神经元中的多巴脱羧酶活性。”标记化合物和放射性药物杂志。

Kawai K., et al.: "Effect of Esterification on Cerebral Accumulation of Radiopharmaceuticals with Carboxylic Acid"Journal of Labelled Compounds and Radiopharmaceuticals. 42. 423-425 (1999)

Kawai K.等人：“酯化对羧酸放射性药物在脑内累积的影响”标记化合物和放射性药物杂志。

Shikano N., Kawai K., et al.: "3-[^<123>I]Iodo-a-methyl-L-tyrosine as a substrate of human L-type amino acid transporter-1"Journal of Labelled Compounds and Radiopharmaceuticals. 44. 354-356 (2001)

Shikano N.、Kawai K.等人：“3-[^ 123 I]碘-a-甲基-L-酪氨酸作为人L-型氨基酸转运蛋白-1的底物”标记化合物杂志和

Flores II L.G., Kawai K. Nakagawa M, Shikano N., Jinnouchi S., Tamura S., Watanabe K., Kubodera A: "A New Radio pharmaceutical for the Cerebral Dopaminergic Presynaptic Function: 6-Radioiodinated L-meta-Tyrosine"J. Cereb. Blood Flow Metab. 20. 207-212 (20

Flores II L.G.、Kawai K. Nakakawa M、Shikano N.、Jinnouchi S.、Tamura S.、Watanabe K.、Kubodera A：“一种用于脑多巴胺能突触前功能的新型放射性药物：6-放射性碘化 L-间位酪氨酸”