Development of optically active radioligand for biomedical imaging of neurotrasmission

利用核医学成像技术和放射性配基进行动态生物成像是阐明神经传递过程的有效方法。在这项研究中，123-I用于核医学成像的优越的辐射性能促使我们合成了一种放射性碘化合物作为用于成像的放射性配体。在分子设计中，由于观察到光学异构体对受体和酶的亲和力有很大差异，因此对光学异构体给予了特别关注。为了评价单胺氧化酶(MAO)在体内的活性，我们分别合成了MAO A的6位碘化环丙氨酸类似物(6ICG)和MAO B的4位碘化RO16-6491类似物(4RO)。每种化合物对相应的酶都表现出很高的亲和力和选择性。此外，注射放射性配基后的脑放射性摄取与酶活性之间也有很好的相关性。为了对烟碱能受体进行显影，合成了一种5-碘-5-碘-A85380(5IA)，并将其作为研究脑烟碱受体的放射性配体。结合亲和力实验结果表明，5IA的亲和力是S烟碱的10倍。在小鼠和大鼠的局部脑分布研究表明，125-I-5IA在丘脑中聚集密集，皮质居中，在小脑中聚集较少。胞苷治疗后，脑内明显的局部分布减少，分布均匀。研究表明，放射性碘标记的6ICG、4RO和5IA是进行脑神经传递活体成像研究的潜在放射性配基。

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.