Exploring occupancy of dopamine D3 receptor by buspirone in humans using positron

描述（由申请人提供）：药物成瘾是美国公共卫生和安全问题，迫切需要改进治疗方法，如靶向药物治疗。临床前数据提供了证据表明多巴胺D3受体（DRD 3）拮抗作用可降低成瘾相关行为。丁螺环酮是FDA批准的抗焦虑药，其作为5-羟色胺部分激动剂，但最近被确定为DRD 3拮抗剂。正电子发射断层扫描（PET）成像允许测量体内的神经化学物质。PET已成为神经科学家可视化和定位受体并估计药物配体对受体的占用的有力工具。成像过程需要注射与目标蛋白（例如多巴胺D3受体）结合的正电子发射放射性示踪剂（例如[11 C]-（+）-PHNO），然后使用PET扫描仪测量这种结合。[11 C]-（+）-PHNO是唯一允许测量人类多巴胺D3受体占有率的配体。在这里，我们将确定丁螺环酮在人体治疗剂量下是否显著占据DRD 3。这些研究将使基础科学发现转化为临床验证。我们的长期目标将是确定丁螺环酮作为烟草依赖干预的可能用途。 公共卫生相关性：丁螺环酮是FDA批准的抗焦虑药，其作为5-羟色胺部分激动剂，但最近被鉴定为多巴胺D3拮抗剂。此外，最近的脑成像方法已经被开发，允许测量人类的多巴胺D3受体。本项目将确定丁螺环酮对人体多巴胺D3受体的剂量占用关系。

DESCRIPTION (provided by applicant): Drug addiction is a US public health and safety concern, urging improved treatment approaches such as targeted pharmacotherapies. Preclinical data have provided evidence that dopamine D3 receptor (DRD3) antagonism decreases addiction-relevant behaviour. Buspirone is an FDA-approved anxiolytic which acts as a serotonin partial agonist but has been recently identified as a DRD3 antagonist. Imaging with positron emission tomography (PET) permits the measurement of neurochemicals in vivo. PET has become a powerful tool for neuroscientists to visualize and localize receptors and estimate receptor occupancy by drug ligands. The process of imaging requires the injection of a positron-emitting radiotracer (e.g. [11C]-(+)-PHNO) that binds to the protein of interest (e.g. dopamine D3 receptors) followed by the measurement of this binding using the PET scanner. [11C]-(+)-PHNO is the only ligand allowing to measure dopamine D3 receptors occupancy in humans. Here, we will determine if buspirone significantly occupies the DRD3 at therapeutic doses in humans. These studies will allow for the translation of basic science discoveries into clinical validation. Our long term goal will be to determine the possible use of buspirone as an intervention for tobacco dependence. PUBLIC HEALTH RELEVANCE: Buspirone is an FDA-approved anxiolytic which acts as a serotonin partial agonist but has been recently identified as a dopamine D3 antagonist. Furthermore, recent brain imaging approaches have been developed allowing to measure dopamine D3 receptors in humans. The present project will determine the dose-occupancy relationship of buspirone for the dopamine D3 receptor in humans.