Development of optically active radioligand for biomedical imaging of neurotrasmission

利用核医学成像技术和放射性配体进行动态生物成像，是阐明神经传递过程的有效方法。在本研究中，123-I的上级辐射特性促进了我们合成放射性碘标记化合物作为用于成像的放射性配体。在分子设计中，特别注意光学异构现象，因为在光学异构体之间观察到对受体和酶的亲和力存在很大差异的情况。为了评价单胺氧化酶（monoamine oxidase，MAO）在体内的活性，我们分别合成了6位碘化的氯吉兰（clorgyline）类似物（6ICG）和4位碘化的Ro 16 - 6491类似物（4Ro）。每种化合物对相应的酶表现出高亲和力和选择性。此外，在注射放射性配体后的脑放射性摄取与酶活性之间观察到良好的相关性。为了研究烟碱胆碱能受体的显像，合成了一种放射性碘标记的烟碱类似物5-iodo-A85380（5IA），并评价了所得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。在小鼠和大鼠中的区域脑分布研究揭示了125-I-5IA的蓄积在丘脑中是密集的，在皮质中是中等的，而在小脑中不太明显。用胞苷处理后，明显的区域性脑分布减少并均匀化。收集的数据表明，放射性碘标记的6ICG，4Ro和5IA是潜在的放射性配体在体内成像研究的脑神经传递。

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.