Development of optically active radioligand for biomedical imaging of neurotrasmission

用于神经传递生物医学成像的光学活性放射性配体的开发

基本信息

批准号：
10470474
负责人：
SAJI Hideo
金额：
$ 6.78万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Dynamic biological imaging using nuclear medical imaging technique and the radioligand is effective for elucidation of the process of neurotransmission. In this study, the superior radiation properties of 123-I for nuclear medical imaging promoted us to synthesize a radioiodinated compound as a radioligand for imaging. In the molecular design, particular attention was given to optical isomerism since there are cases where a great difference for the affinity for receptors and enzymes is observed between optical isomers. To evaluate the activity of monoamine oxidase (MAO) in vivo, we synthesized a clorgyline analog iodinated at 6-position (6ICG) for MAO A and a Ro 16-6491 analogs iodinated 4-position (4Ro) for MAO B, respectively. Each compound showed a high affinity and selectivity for a corresponding enzyme. Furthermore, a good correlation was observed between the cerebral uptake of radioactivity after injection of radioligand and enzymatic activity. For the imaging of nicotinic cholinergic receptors, a radioiodinated nicotine analog iodinated at 5-position of the pyridine ring,5-iodo-A85380 (5IA) was synthesized and the obtained 5IA was evaluated as a potential radioligand for investigating brain nicotinic receptors. The results of binding affinity experiments revealed that the affinity of 5IA was 10-fold higher than that of (S)-nicotine. Regional cerebral distribution studies in mice and rats disclosed that the accumulation of 125-I-5IA was dense in the thalamus, intermediate in the cortex and less marked in the cerebellum. The marked regional cerebral distribution was reduced and uniformalized by the treatment with cytidine. Gathered data indicate that radioiodinated 6ICG, 4Ro, and 5IA are potential radioligands for in vivo imaging studies of cerebral neurotransmission.

使用核医学成像技术和放射性配体的动态生物成像可有效阐明神经传递过程。在这项研究中，123-I在核医学成像方面的优异辐射特性促使我们合成放射性碘化合物作为成像用放射性配体。在分子设计中，特别关注光学异构体，因为在某些情况下观察到光学异构体之间对受体和酶的亲和力存在很大差异。为了评估体内单胺氧化酶 (MAO) 的活性，我们分别合成了 MAO A 的 6 位碘化氯吉林类似物 (6ICG) 和 MAO B 的 4 位碘化 Ro 16-6491 类似物 (4Ro)。每种化合物对相应的酶都表现出高亲和力和选择性。此外，注射放射性配体后大脑对放射性的摄取与酶活性之间观察到良好的相关性。为了烟碱胆碱能受体的成像，合成了在吡啶环5位碘化的放射性碘化烟碱类似物5-碘-A85380（5IA），并评估所得5IA作为研究脑烟碱受体的潜在放射性配体。结合亲和力实验结果表明，5IA的亲和力比(S)-尼古丁高10倍。对小鼠和大鼠的区域脑分布研究表明，125-I-5IA 的积累在丘脑中密集，在皮质中居中，在小脑中较少。通过胞苷治疗，显着的局部脑分布减少并均匀化。收集的数据表明，放射性碘化 6ICG、4Ro 和 5IA 是脑神经传递体内成像研究的潜在放射性配体。