Development of in vivo dynamic and noninvasive imaging methodology of neurotransmission system with optically active radioligand.

利用光学主动放射配体和核医学成像系统，发展了活体动态无创神经传递系统研究方法。最近在包括阿尔茨海默病在内的各种疾病患者的大脑中报道了尼古丁乙酰胆碱受体（nachr）密度的变化。因此，在吡啶环5位碘化的a -85380类似物5-碘-3-（2(S)-偶氮基甲氧基）吡啶（5IA）被评价为核医学成像方法研究脑nachr的放射性配体。结合数据显示，5IA与A-85380的亲和力相同，比(-)-尼古丁的亲和力高7倍以上，并且5IA选择性结合α4β2 nAChR亚型。在大鼠体内的生物分布研究表明[^<125>I]5IA的脑吸收是快速而深刻的。大鼠大脑区域分布研究表明，[^<125 b>]5IA的积累与高亲和力nachr的密度一致。nAChR激动剂的使用减少了[^<125>I]5IA的摄取，并导致整个大脑的放射性水平相似。[^<125>I]5IA结合位点与未标记的5IA可饱和。此外，在普通狨猴中使用[^<123 b> I]5IA进行的SPECT研究表明，高亲和的nAChR在体内成像放射配体具有适当的脑摄取和区域定位。最近的研究表明，去甲肾上腺素转位蛋白（NET）在几种脑和心血管疾病中的变化。因此，基于构效关系，(R)- n - meyl -3-(2- idophenoxy)-3-苯丙胺（MIPP）被开发为一种放射性配体，用于核医学成像方法研究脑和心肌NET。结合数据显示，(R)-MIPP的亲和力是托莫西汀和(S)-对映体的2倍和100以上，对NET的选择性高。在大鼠体内的生物分布研究也显示了NET的高亲和力和选择性。这些结果表明[^<123>I]5IA是一种很有前途的放射性配体，可用于人脑和心肌NET的核医学研究。少

The method for in vivo dynamic and noninvasive investigation of neurotransmission system was developed using optically active radioligand and nuclear medical imaging system.1. Changes in the density of nicotinic acethylcholine receptors (nAChRs) have recently been reported in the brains of patients with various disorders, including Alzheimer's disease. Thus, 5-Iodo-3-(2(S)-azetidinylmethoxy)Pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radioligand for investigating brain nAChRs by nuclear medical imaging methodology. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (-)-nicotine, and that 5IA bound selectively to the α4β2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [^<125>I]5IA was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [^<125>I]5IA was consistent wit … More h. the density of high affinity nAChRs. Administration of the nAChR agonists reduced the uptake of [^<125>I]5IA and resulted in similar levels of radioactivity throughout the brain. [^<125>I]5IA binding sites were shown to be saturable with unlabeled 5IA. Furthermore, SPECT studies with [^<123>I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR in vivo imaging radioligand.2. Recent studies demonstrated changes of norepinephrine transpoter (NET) in several cerebral and cardiovascular diseases. Thus, (R)-N-metheyl-3-(2- idophenoxy)-3-phenylpropamine (MIPP) was developed based on the structure-activity relationship as a radioligand for investigating brain and myocardial NET by nuclear medical imaging methodology. showed The binding data revealed that the affinity of (R)-MIPP was twice and more than 100 higher than that of tomoxietine and (S)-enatiomer, and selectivity to NET was high. Biodistribution studies in rats also indicated high affinity and selectivity for NET. These results suggested that [^<123>I]5IA is a promising radioligand for nuclear medical studies of brain and myocardial NET in-human subjects. Less