DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)

描述(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)脑成像的正电子发射断层扫描(PET)放射性示踪剂。PDE10A在纹状体中等大小的棘突投射神经元(MSN)中高水平表达，在cGMP和cAMP的调节中起关键作用。纹状体PDE10A水平的异常影响纹状体的输出，并可能在精神分裂症、亨廷顿病(HD)和其他精神障碍的病理生理学中起重要作用。纹状体PDE10A水平的降低与HD的严重程度相关，而抑制PDE10A已被认为是治疗精神分裂症及相关疾病的一种新的治疗策略。因此，PDE10A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。为了实现这个项目的目标，我们首先用C-11标记了一种具有代表性的PDE10A化合物，2-((4-(1-[11C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-(苯氧基)-甲基)喹啉([11C]MP-10)。MP-10是一种高效的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)。我们还成功地对MP-10进行了结构修饰，得到了含氟类似物TuJF103(IC50=0.27 nm)。[11C]MP-10和[18F]TUJF103在大鼠体内的初步生物分布评价，以及这两种放射性示踪剂在猴子体内的microPET成像研究表明，靶区(纹状体)和参照区(小脑)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脑和血液的代谢物分析表明，存在亲脂的放射性标记代谢物，这些代谢物在大脑中积累非特异性。这些代谢物可能会限制[11C]MP-10或[18F]TUJF103作为PDE10A成像的新型PET示踪剂的临床应用。为了克服这些担忧，这项建议将优化MP-10的结构，以合成对PDE10A具有高亲和力和选择性的新类似物；放射性标记与C-11或F-18的候选放射性标记，然后使用体内方法验证用于脑内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)通过优化MP-10的结构合成新的类似物；(2)体外测量新类似物的亲和力；(3)标记与C-11或F-18具有高亲和力(IC50和lt；15 nm)和高选择性(&gt；100倍)的配体；(4)进行放射性示踪剂在大鼠体内的生物分布和脑摄取研究，以确定至少两个有希望的候选配体。R33组件的具体目标将是在灵长类动物中继续评估这些候选放射性示踪剂，目标是确定一种适合翻译临床评估的PET示踪剂，用于用PET对大脑中的PDE10A进行成像。 公共卫生相关性：亨廷顿氏病是一种进行性神经功能障碍，包括运动、认知和精神障碍。据报道，超过15,000名美国人患有HD。至少其他15万人有50%的风险患上这种疾病，还有数千名他们的亲属生活在他们可能患上HD的可能性中。PDE10A的PET放射性示踪剂可以帮助医生基于对亨廷顿病患者PDE10A水平的PET测量来量化亨廷顿病的进展。

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. PUBLIC HEALTH RELEVANCE: Huntington's disease is a progressive neurological disorder of motor, cognitive, and psychiatric disturbances. It was reported more than 15,000 Americans have HD. At least other 150,000 have a 50% risk of developing the disease and thousands more of their relatives live with the possibility that they might develop HD. A PET radiotracer of PDE10A may help physician to quantify the progression of Huntington Disease based on the PET measurement of PDE10A level in patients with the Huntington disease patients.