DEVELOPMENT OF A NOVEL PET LIGAND FOR DETECTING OXYTOCIN RECEPTORS IN BRAIN

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们成功地合成了四种不同的铅候选PET化合物，包括未标记的氟化和碘化版本。 我们确定了测试化合物对人加压素和催产素受体的相对亲和力。 结果表明，每种修饰形式的先导化合物对人催产素受体具有高度选择性，对人加压素受体的结合亲和力为500 nM。 我们的候选物氟-18配体被标记并使用大鼠模型进行组织收获研究。 脑穿透的结果不确定，再次发现log P值在预期范围内。 我们选择在我们的microPET/CT扫描仪上使用大鼠模型进行体内PET扫描。 四只大鼠的PET扫描显示没有脑渗透，但在垂体中出现了显著的配体摄取，其中催产素和加压素在外周释放之前储存在垂体中。我们的候选碳-11配体标记，并通过microPET/CT在大鼠模型中进行研究。 再次发现亲脂性在所需范围内，并且尽管在所有候选物中具有最低分子量，但该化合物未显示渗透到脑中。 我们对最初的结果感到失望，但相信我们有一个健全的计划继续下去，并乐观地认为，我们将成功地开发PET配体。 计划包括尝试通过共注射甘露醇渗透血脑屏障，以及生产具有较小分子量的其他小分子配体的衍生物或有穿透血脑屏障的证据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We successfully synthesized four variations of lead candidate PET compounds, including unlabeled fluorinated and iodinated versions. We determined the relative affinity of the test compounds for human vasopressin and oxytocin receptor. Results indicated that each of the modified versions of lead compound was highly selective for human oxytocin receptor, with binding affinities 500 nM for human vasopressin receptor. Our candidate fluorine-18 ligand was labeled and subjected to tissue harvest studies using rat models. Results for brain penetration were inconclusive and log P values were again found to be in desired range. We opted to perform in vivo PET scans using rat models on our microPET/CT scanner. PET scans on four rats displayed no brain penetration, but significant uptake of ligand appeared in the pituitary gland where oxytocin and vasopressin are stored prior to peripheral release. Our candidate carbon-11 ligand was labeled and investigated in rat model via microPET/CT. Once again the lipophilicity was found to be in desired range, and despite having lowest molecular weight of all candidates, the compound did not display penetration into the brain. We were disappointed in initial results but believe that we have a sound plan to continue and are optimistic that we will succeed in developing a PET ligand. Plan includes trying to permeablize the blood-brain barrier by co-injection mannitol, as well as producing derivatives of other small molecule ligands with smaller molecular weights or there is evidence of penetration of the blood brain barrier.