Dopamine Transporter Imaging with Fluorine-18 PET

描述(申请人提供)：正电子发射断层扫描(PET)是 敏感和特定的非侵入性成像技术，可以提供 关于体内神经递质系统的功能状态的信息。 最近的努力集中在基于PET的放射性示踪剂的开发上 多巴胺转运体(DAT)丰度和药理学研究中的应用 DAT密度和功能的变化已牵涉到 帕金森、S病等神经退行性疾病和神经精神疾病， 重度抑郁症、亨廷顿舞蹈症、精神分裂症和注意力 缺陷多动障碍(ADHD)。我们早期的研究主要集中在 氟-18标记的托烷衍生物，如FP-C1T，其中N-甲基 托烷的基团被[S18FJ氟丙基]取代。在.期间 第一阶段项目，我们描述了大脑单胺转运体结合 一系列新型含氟烷基托烷衍生物的亲和力 显示出比FP-C1T更高的DAT亲和力和选择性。这些新的配体是 ~8F标记正电子发射体示踪剂的发展前景 人脑的临床影像DAT。 我们在这个二期项目上的目标是进一步综合和 新的N-或0-氟烷基托烷衍生物的药理学评价 查看一步简化的18F-放射性标记。最有希望的 将评估化合物的物理化学性质(亲脂性)。一个 18F标记托烷衍生物的简便快速合成方法 为最有希望的化合物(S)开发。本系列中的先导化合物 (目前BRL-308)将通过PET成像和药代动力学进行评估， 非人灵长类动物。 建议的商业应用：不可用

DESCRIPTION (provided by applicant):Positron emission tomography (PET) is sensitive and specific non-invasive imaging technology that can provide information about the functional status of neurotransmitter systems in-vivo. Recent efforts have focused on the development of PET-based radiotracers for use in studies of the dopamine transporter (DAT) abundance and pharmacology Changes in the density and function of DAT have been implicated in neurodegenerative and neuropsychiatric diseases such as Parkinson?s disease, major depression, Huntington's chorea, schizophrenia, and attention deficit-hyperactivity disorders (ADHD). Our earlier studies have focused on fluorine-18 labeled tropane derivatives, such as FP-C1T, in which the N-methyl group of the tropane was replaced by a [S18FJ fluoropropyl group. During the Phase I project, we characterized the cerebral monoamine transporter binding affinity of a series of novel fluoralkyl-containing tropane derivatives, which showed higher DAT affinity and selectivity than FP-C1T. These new ligands are attractive candidates for development of ?8F-labeled PET radiotracers for clinical imaging DAT in human brain. Our objectives on this Phase II project are to further synthesize and pharmacologically evaluate novel N- or 0-fluoroalkyl tropane derivatives with a view toward one-step simplified 18F-radiolabeling. The most promising compounds' physiochemical properties (lipophilicity) will be evaluated. A facile and rapid method of synthesis of 18F labeled tropane derivatives will be developed for the most promising compound(s). The lead compound in this series (presently BRL-308) will be evaluated by PET imaging and pharmacokinetics, in non-human primates. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE