DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)

开发用于磷酸二酯酶 10A (PDE10A) 成像的宠物试剂

• 批准号: 8661060
• 负责人: Zhude Tu
• 金额: $ 46.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661060
• 关键词: Affect; Affinity; American; Biodistribution; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Central Nervous System Diseases; Cerebellum; Clinic; Clinical; Cognitive; Corpus striatum structure; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Disease; Evaluation; Fluorine; Functional disorder; Goals; Huntington Disease; Image; In Vitro; Inhibitory Concentration 50; Isoenzymes; Isotopes; Kinetics; Label; Lead; Life; Ligands; Link; Measurement; Measures; Mental disorders; Metals; Methods; Monkeys; Motor; Neuraxis; Neurons; Neurosciences Research; Nitrogen; Output; Oxygen; Patients; Pharmacology; Phenols; Physicians; Physiology; Play; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Primates; Radiolabeled; Rattus; Regulation; Relative (related person); Reporting; Research; Risk; Role; Schizophrenia; Severities; Structure; Sulfur; Time; Tracer; Validation; analog; base; enzyme activity; imaging modality; improved; in vivo; inhibitor/antagonist; innovation; methyl group; nervous system disorder; non-invasive imaging; novel; novel therapeutics; patient oriented research; phosphoric diester hydrolase; public health relevance; quinoline; radioligand; radiotracer; receptor; research clinical testing; success; tool; treatment strategy; uptake

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a Positron Emission Tomography (PET) radiotracer for brain imaging of the cyclic nucleotide phosphodiesterase 10A (PDE10A). PDE10A is specifically expressed in the brain with high levels in striatal medium-sized spiny projection neurons (MSN) where it plays a critical role in the regulation of both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). Abnormal striatal levels of PDE10A affect striatal output and may contribute substantially to the pathophysiology of schizophrenia, Huntington's disease (HD) and other mental disorders. Decreased striatal PDE10A level has been correlated with the severity of HD, while inhibition of PDE10A has been proposed as a novel therapeutic strategy for treating schizophrenia and related conditions. Thus, a PET radiotracer for PDE10A would be a valuable tool for clinical neuroscience research. To achieve the goal of this project, we first radiolabeled a representative PDE10A compound, 2-((4-(1-[11C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3- yl)phenoxy)-methyl)quinoline ([11C]MP-10) with C-11. MP-10 is a high potency PDE10A inhibitor (IC50 = 0.37 nM) with high selectivity (1000 fold) for PDE10A vs. other PDEs and CNS receptors. We also successfully modified the structure of MP-10 to make a fluorine analogue, TuJF103 (IC50 = 0.27 nM). Preliminary biodistribution evaluation of [11C]MP-10 and [18F]TUJF103 in rats, and microPET imaging studies of both radiotracers in monkeys displayed good contrast between the target (striatal) and the reference (cerebellum) region. However, analysis of the time-activity curves of striatum and cerebellum and subsequent metabolite analysis of rat brain and blood indicated the presence of lipophilic radiolabeled metabolites that accumulate non-specifically in the brain. Such metabolites could limit the clinical utility of either [11C]MP-10 or [18F]TUJF103 as novel PET tracers for imaging PDE10A. To overcome such concerns, this proposal will optimize the structure of MP-10 to synthesize new analogues with high affinity and selectivity for PDE10A; radiolabel lead candidates with C-11 or F-18 and then use in vivo methods to validate optimal PET radiotracers for imaging PDE10A in the brain. Consequently, the specific aims of the R21 component include: (1) synthesize new analogues by structural optimization of MP-10; (2) measure the affinities of new analogues in vitro; (3) radiolabel the ligands having high affinities (IC50<15 nM) and high selectivity (> 100 fold) with C-11 or F-18; (4) conduct biodistribution and brain uptake studies of radiotracers in rats to identify at least two promising candidates. The specific aims of the R33 component will be the continued evaluation of these candidate radiotracers in primates with the goal of identifying a PET tracer suitable for translational clinical evaluation for imaging PDE10A in the brain with PET.

描述（由申请人提供）：该项目的最终目标是开发一种用于环核苷酸磷酸二酯酶 10A (PDE10A) 脑部成像的正电子发射断层扫描 (PET) 放射性示踪剂。 PDE10A 在大脑纹状体中型多刺投射神经元 (MSN) 中高水平表达，在环磷酸鸟苷 (cGMP) 和环磷酸腺苷 (cAMP) 的调节中发挥着关键作用。 PDE10A 纹状体水平异常会影响纹状体输出，并可能对精神分裂症、亨廷顿病 (HD) 和其他精神障碍的病理生理学产生重大影响。纹状体 PDE10A 水平降低与 HD 的严重程度相关，而抑制 PDE10A 已被提议作为治疗精神分裂症和相关疾病的新治疗策略。因此，PDE10A 的 PET 放射性示踪剂将成为临床神经科学研究的宝贵工具。为了实现该项目的目标，我们首先对代表性的PDE10A化合物2-((4-(1-[11C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)进行放射性标记-甲基)喹啉([11C]MP-10)与C-11。 MP-10 是一种高效 PDE10A 抑制剂 (IC50 = 0.37 nM)，与其他 PDE 和 CNS 受体相比，对 PDE10A 具有高选择性（1000 倍）。我们还成功修饰了 MP-10 的结构，制备了氟类似物 TuJF103 (IC50 = 0.27 nM)。 [11C]MP-10 和 [18F]TUJF103 在大鼠中的初步生物分布评估以及两种放射性示踪剂在猴子中的 microPET 成像研究显示目标（纹状体）和参考（小脑）区域之间具有良好的对比度。然而，对纹状体和小脑的时间-活动曲线的分析以及随后对大鼠大脑和血液的代谢物分析表明，存在非特异性在大脑中积累的亲脂性放射性标记代谢物。此类代谢物可能会限制 [11C]MP-10 或 [18F]TUJF103 作为用于 PDE10A 成像的新型 PET 示踪剂的临床应用。为了克服这些担忧，本提案将优化MP-10的结构，合成对PDE10A具有高亲和力和选择性的新类似物；使用 C-11 或 F-18 放射性标记先导候选物，然后使用体内方法验证用于大脑中 PDE10A 成像的最佳 PET 放射性示踪剂。因此，R21组分的具体目标包括：（1）通过MP-10的结构优化合成新的类似物； (2) 体外测定新类似物的亲和力； (3)用C-11或F-18对具有高亲和力(IC50<15nM)和高选择性(>100倍)的配体进行放射性标记； (4) 在大鼠体内进行放射性示踪剂的生物分布和脑摄取研究，以确定至少两种有希望的候选物。 R33 组件的具体目标是在灵长类动物中持续评估这些候选放射性示踪剂，目的是确定一种适合转化临床评估的 PET 示踪剂，用于使用 PET 对大脑中的 PDE10A 进行成像。