Development of optically active radioligand for in vivo investigation of brain nicotine receptors.

最近有报道称，患有各种疾病（包括阿尔茨海默病）的患者的大脑中尼古丁受体密度发生了变化。这些观察结果激发了人们对核医学成像技术（如SPECT）在体内无创成像脑烟碱受体分布的兴趣。在本研究中，123-I对SPECT的优越辐射特性促使我们合成了一种具有高受体亲和力的放射性碘化尼古丁类似物。因此，合成了在吡啶环5位碘化的(S) -尼古丁类似物(S) 5-碘尼古丁（INC），并通过SPECT评价其作为研究脑尼古丁受体的潜在放射性药物。合成的[125I] - (S) - inc具有高比放射性。INC对脑尼古丁受体的结合数据表明，INC的亲和力与(S) -尼古丁相同，比(R) -对映体高80倍。在小鼠体内的生物分布研究表明，大脑对INC的吸收是迅速而深刻的。通过放射自显像对大鼠大脑区域分布的研究表明，[125-I] -INC的积累与体外研究中报道的尼古丁受体的分布密切相关。(R) -对映体比(S) -对映体表现出更快的脑冲洗和更小的脑区域分布。因此，INC在体内与脑尼古丁受体结合，因此123-I-INC可能是一种潜在的放射性配体，可用于SPECT在体内脑尼古丁受体研究。

Changes in the density of nicotine receptors have recently been reported in the brains of patients with various disorders, including Alzheimer's disease. These obsevations have stimulated interest in means of imaging the distribution of brain 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 prompted us to synthesize a radioiodinated nicotine analog with high receptor affinity. Thus, (S) 5-iodonicotine (INC), an (S) -nicotine analog iodinated at the 5-position of the pyridine ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nicotine receptors by SPECT.[125I] - (S) -INC was synthesized with high specific radioactivity. The binding data of INC for brain nicotine receptors revealed that the affinity of INC was the same as that of (S) -nicotine and 80-fold higher than the (R) -enantiomer. Biodistribution studies in mice disclosed that the brain uptake of INC was rapid and profound. Regional cerebral distribution studies in rats by autoradiography disclosed that the accumulation of [125-I] -INC was correlated well with the distribution of nicotine receptors reported from in vitro studies. (R) -enantiomer showed more rapid washout the brain and smaller regional cerebral distribution than (S) -enantiomer. Thus, INC bound to brain nicotine receptors in vivo and therefore 123-I-INC may be a potential radioligand for use in in vivo cerebral nicotinic receptor studies by SPECT.