18F-LABELED BENZAMIDES FOR DOPAMINE-D2 STUDIES USING PET

人体体内神经受体的正电子发射断层扫描研究 在帮助识别受体缺陷的作用方面大有可为 很多疾病。这项研究旨在开发放射性药物。 它们定位于大脑的离散区域，基于它们的选择性 突触后多巴胺D2受体的亲和力。18F和11C标记 螺环酮及其类似物继续用于D2的正电子发射计算机断层扫描研究 受体尽管存在非选择性、高非特异性等问题 氟化环的放射化学合成困难 螺螺酮。缺乏明显更好的D2配体是主要的 使用螺螺环酮的原因。这里提出的工作是针对 具有显著改进作用的试剂的合成与评价 性能优于螺环丙酮。这项工作的目标是演示 这些药物在未来的人体活体研究中的适用性。 预计这些放射性药物的发展，他们的 活体表征，它们的使用最终将有助于研究 帕金森氏病和精神分裂症 多巴胺能传递被认为起了一定的作用。此外，这些 在研究D2系统的各种变化时，试剂很可能被证明是有用的 在衰老过程中。 非放射性苯环氟烷基苯甲酰胺化合物将 竞争置换法合成及其体外表征 捆绑技术。具有合适的体外结合能力的试剂 特性将在体内进一步评估，以确定它们作为 用于多巴胺D2定量PET研究的放射性药物 受体。这些配体所需的体内特性包括： 良好的大脑渗透率，为PET提供足够的计数统计数据 研究；D2受体富集区的区域定位；保留 在这些特定区域开展活动，以获得足够的PET数据 获取；快速清除非目标区域的非特定摄取 如小脑；多巴胺D2的药理特异性 受体；摄取部位饱和度；缺乏亲脂代谢物 血液和大脑中的代谢物很少。 那些表现出选择性的、有效的结合位点亲和力的化合物 将用氚放射性标记D2受体。标有氚的 化合物将用于进一步的研究，以评估体外结合 代理的参数。那些化合物显示出很好的前景 体外和体内的特性将被标记为高特异性 活动18F(一个半衰期为110分钟的短寿命正电子发射体)和 用于猴子正电子发射断层扫描的区域定位研究。这个 该试剂的多巴胺D2位点密度和离解结合常数 将会被确定。在动物身上进行的宠物研究将确定 作为潜在多巴胺D2受体配体的化合物的研究 在人类实验对象中。一系列的试点试验将在 正常受试者体内18F标记配体的性质评价 以确定多巴胺D2结合参数。

Positron emission tomography (PET) studies of neuroreceptors in vivo in man hold great promise in helping to identify the role of receptor defects in many diseases. This research is aimed at developing radiopharmaceuticals which localize in discrete regions of the brain based upon their selective affinity for the postsynaptic dopamine D2 receptor. 18F- and 11C-labeled spiperone and its analogs continue to be used for PET studies of the D2 receptor despite problems such as non-selectivity, high non-specific binding, and the difficult radiochemical synthesis of ring fluorinated spiperone. The absence of a substantially better D2 ligand is a primary reason for the use of spiperone. The work proposed here is aimed at the synthesis and evaluation of agents possessing substantially improved properties over spiperone. The goal of this work is to demonstrate the applicability of these agents for future in vivo studies in human subjects. It is anticipated that the development of these radiopharmaceuticals, their in vivo characterization, and their use will eventually aid in the study of Parkinson's disease and schizophrenia in which abnormalities in dopaminergic transmission are believed to play a role. In addition, these agents may well prove useful in studying various changes of the D2 system in aging. Non-radioactive phenyl ring fluoroalkylated benzamide compounds will be synthesized and the characterized in vitro using competitive displacement binding techniques. Those agents possessing suitable in vitro binding properties will be further assessed in vivo to determine their potential as radiopharmaceuticals for quantitative PET studies of the dopamine D2 receptor. The desired in vivo characteristics of these ligands include: good brain penetration to provide adequate counting statistics for PET studies; regional localization in D2 receptor rich areas; retention of activity in those specific areas to allow for adequate PET data acquisition; rapid clearance of non-specific uptake in non-target areas such as the cerebellum; pharmacological specificity for the dopamine D2 receptor; uptake site saturability; absence of lipophilic metabolites in the blood; and few metabolites in the brain. Those compounds which demonstrate a selective, potent binding site affinity to the D2 receptor will be radiolabeled with tritium. The tritium-labeled compound will be used in further studies to assess in vitro binding parameters of the agent. Those compounds displaying promising characteristics in vitro and in vivo will be labeled with high specific activity 18F (a short-lived positron emitter with a 110 min half-life) and utilized in PET regional localization investigations in monkeys. The dopamine D2 site densities and dissociation binding constant for the agent will be determined. PET studies in animals will determine the efficacy of the compounds as potential dopamine D2 receptor ligands for investigations in human subjects. A series of pilot experiments will be conducted in normal subjects to assess the properties of the 18F-labeled ligands in vivo to determine dopamine D2 binding parameters.