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: 8551075
• 负责人: Zhude Tu
• 金额: $ 44.87万
• 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/8551075
• 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; 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）：本项目的最终目标是开发用于环核苷酸磷酸二酯酶10A（PDE 10A）脑成像的正电子发射断层扫描（PET）放射性示踪剂。PDE 10A在脑中特异性表达，在纹状体中等大小的多刺投射神经元（MSN）中具有高水平，其中其在环鸟苷酸（cGMP）和环腺苷酸（cAMP）的调节中起关键作用。PDE 10 A的异常纹状体水平影响纹状体输出，并且可能实质上促成精神分裂症、亨廷顿病（HD）和其他精神障碍的病理生理学。纹状体PDE 10A水平的降低与HD的严重程度相关，而PDE 10A的抑制已被提出作为治疗精神分裂症和相关病症的新的治疗策略。因此，PDE 10A的PET放射性示踪剂将是临床神经科学研究的有价值的工具。为了实现该项目的目标，我们首先用C-11放射性标记了代表性PDE 10A化合物2-（（4-（1-[11 C]甲基-4-（吡啶-4-基）-1H-吡唑-3-基）苯氧基）-甲基）喹啉（[11 C]MP-10）。MP-10是一种高效PDE 10A抑制剂（IC 50 = 0.37 nM），与其他PDE和CNS受体相比，对PDE 10A具有高选择性（1000倍）。我们还成功地修改了MP-10的结构，以制备氟类似物TuJF 103（IC 50 = 0.27 nM）。[11 C]MP-10和[18 F] TUJF 103在大鼠中的初步生物分布评价以及两种放射性示踪剂在猴中的microPET成像研究显示靶（纹状体）和参考（小脑）区域之间的对比度良好。然而，纹状体和小脑的时间-活性曲线分析以及随后的大鼠脑和血液代谢物分析表明，存在非特异性蓄积在脑中的亲脂性放射性标记代谢物。这些代谢物可能限制[11 C]MP-10或[18 F] TUJF 103作为用于成像PDE 10A的新型PET示踪剂的临床效用。为了克服这些问题，该提案将优化MP-10的结构，以合成对PDE 10A具有高亲和力和选择性的新类似物;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脑中成像PDE 10A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的结构优化来合成新的类似物;（2）在体外测量新类似物的亲和力;（3）放射性标记具有高亲和力的配体（IC 50 <15 nM）和高选择性（> 100倍）;（4）在大鼠中进行放射性示踪剂的生物分布和脑摄取研究，以鉴定至少两种有希望的候选物。R33组件的具体目的是在灵长类动物中继续评价这些候选放射性示踪剂，目的是确定适合用于PET脑中PDE 10A成像的转化临床评价的PET示踪剂。