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

利用光学活性放射性配体和核医学成像系统，建立了在体动态、无创研究神经传递系统的方法.最近有报道称，包括阿尔茨海默病在内的各种疾病患者的大脑中烟碱乙酰胆碱受体（nAChR）密度发生了变化。因此，5-碘-3-（2（S）-氮杂环丁烷甲氧基）吡啶（5IA），一种在吡啶环5位碘化的A-85380类似物，被评价为通过核医学成像方法研究脑nAChR的放射性配体。结合数据显示，5IA的亲和力与A-85380相同，比（-）-尼古丁高7倍以上，并且5IA选择性地结合α4β2 nAChR亚型。大鼠体内的生物分布研究表明，[^ I]5IA的脑摄取<125>迅速而深刻。大鼠局部脑分布研究表明，[^<125>I]5IA的蓄积与 ...更多信息 H.高亲和力nAChR的密度。给予nAChR激动剂可降低[^<125>I]5IA的摄取，并导致整个脑中放射性水平相似。[13 <125>I]5IA结合位点显示出可被未标记的5IA饱和。此外，<123>在普通绒猴中使用[^ I]5IA的SPECT研究证明了高亲和力nAChR体内成像放射性配体的适当脑摄取和区域定位。近年来的研究表明，去甲肾上腺素转运蛋白（NET）在多种心脑血管疾病中的变化。因此，基于构效关系，开发了（R）-N-甲基-3-（2-碘苯氧基）-3-苯基丙胺（MIPP）作为通过核医学成像方法研究脑和心肌NET的放射性配体。结果表明，（R）-MIPP与NET的结合亲和力是托莫西汀和（S）-对映体的2倍和100倍以上，且对NET有很高的选择性。在大鼠中的生物分布研究也表明NET具有高亲和力和选择性。这些结果表明，[^<123>I]5IA是一种有前途的放射性配体，用于人类受试者脑和心肌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