Development of optically active radioligand for biomedical imaging of neurotrasmission

利用核医学成像技术和放射配体进行动态生物成像对阐明神经传递过程是有效的。在本研究中，123-I优越的核医学成像辐射特性促使我们合成了一种放射性碘化化合物作为成像放射配体。在分子设计中，特别注意光学同分异构体，因为在光学同分异构体之间观察到对受体和酶的亲和力有很大差异。为了评价单胺氧化酶（MAO）在体内的活性，我们分别合成了6位碘化的clyline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均表现出较高的亲和力和选择性。此外，观察到注射放射性配体后大脑对放射性的摄取与酶活性之间有良好的相关性。为了对尼古丁胆碱能受体进行成像，合成了一种在吡啶环5位碘化的放射性尼古丁类似物5-碘- a85380 (5IA)，并评价该5IA作为研究脑尼古丁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。小鼠和大鼠的大脑区域分布研究表明，125-I-5IA的积累在丘脑密集，在皮层居中，在小脑不明显。胞苷治疗后显著的脑区分布减少并均匀化。收集到的数据表明，放射性碘化的6ICG、4Ro和5IA是脑神经传递体内成像研究的潜在放射性配体。

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.