In vivo investigation of brain nicotine receptors using optically active radioligand

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都存在尼古丁受体密度的变化。这些观察结果激发了人们对利用核医学成像技术(如SPECT)无创性地在体内成像尼古丁受体分布的兴趣。在本研究中，由于123I用于SPECT的优越的辐射性能促使我们合成了一种标记在吡啶5位上的放射性碘化尼古丁，并评价了其作为一种潜在的放射性配体用于脑内尼古丁受体的SPECT研究。放射性碘(S)-5-碘烟碱(INC)是在无载体添加的条件下通过放射性去甲基化反应合成的。用3-H-胱氨酸从大鼠大脑皮层膜上的结合部位移位的方法测定了Inc与脑尼古丁受体的结合亲和力。结合数据显示，INC的亲和力与(S)-尼古丁和80倍…的亲和力相同比(R)-对映体高。用放射自显影对大鼠脑内局部分布的研究表明，125-I-Inc在丘脑中聚集较密集，在皮质和纹状体居中，在小脑中聚集较少。与S对映体相比，125I-(R)-Inc.表现出更快的脑洗脱速度和更广泛的脑组织分布。收集的数据表明，~(123)I-标记的(S)-INC是一种潜在的放射性配体，可用于脑内烟碱受体的SPECT研究。此外，用~(125)I-INC定量放射自显影技术研究了抑制胆碱能投射对烟碱受体功能的影响。在同侧皮质，INC摄取在术后6小时增加，在第7天显著下降。结果表明，大脑皮质尼古丁受体功能在基底前脑大量活动后发生了变化。较少

Changes in the density of nicotinic receptors have recently been reported in the brains of patients with various disorders, including Alzheimer's disease. These observations have stimulated interest in means of imaging the distribution of nicotinic receptors noninvasively in vivo with nuclear medicinal imaging techniques such as SPECT.In this study, the superior radiation properties of 123-I for SPECT promoted us to syntheszed a radioiodinated nicotine anlog iodinated at the 5-position of the pyridine, was synthesized and evaluated as a potential radioligand for investigating brain nicotine receptors by SPECT.Radioiodinated (S)-5-iodonicotine (INC) was synthsized by the radiodestannylation reaction under no-carrier-added conditions. The binding affinity of INC for brain nicotine receptors was measured in terms of displacement of 3-H-cytisine from binding sites in rat cortical membranes. The binding data revealed that the affinity of INC was the same as that of (S)-nicotine and 80-fold … More higher than that of the (R)-enatiomer. Regional cerebral distribution studies in rats by autoradiography disclosed that the accumulation of 125-I-INC was dense in the thalamus, intermediate in the cortex and striatum, and less marked in the cerebellum. 125-I-(R)-INC showed more rapid washout from the brain and less extensive regional cerebral distribution than the (S)-enatiomer. Gathered data indicate that 123-I-labeled (S)-INC is a potential radioligand for use in vivo cerebral nicotinic receptor studies by SPECT.Furthermore, the influence of inhibition of cholinergic projection on the nicotinic receptor function was investigated using quantitative autoradiography with 125-I-INC.Regional cerebral distribution of 125-I-INC was evaluated after selective inhibition of cholinergic neurons in rat basal forbrain using pyruvate dehydrogenase complex inhibitor, 3-bromopyruvic acid (BPA). In ipsilateral cortex, INC uptake increased at 6 hr post surgery and significantly decreased at 7days. The results indicate that nicotine receptor function in cerebral cortex changes after the legion of the basal forebrain. Less