DEVELOPING PET AGENTS FOR IMAGING PHOSPHODIESTERASE 10A (PDE10A)

描述（由申请人提供）：本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在大脑纹状体中等棘突投射神经元（MSN）中特异性高水平表达，在环鸟苷单磷酸（cGMP）和环腺苷单磷酸（cAMP）的调控中起关键作用。纹状体PDE10A水平异常会影响纹状体输出，并可能在很大程度上导致精神分裂症、亨廷顿病（HD）和其他精神障碍的病理生理。纹状体PDE10A水平的降低与HD的严重程度相关，而抑制PDE10A已被提出作为治疗精神分裂症及相关疾病的新治疗策略。因此，PDE10A的PET示踪剂将成为临床神经科学研究的宝贵工具。为了实现本项目的目标，我们首先用C-11对具有代表性的PDE10A化合物2-（（4-（1-[11C]甲基-4-（吡啶-4-基）- 1h -吡唑-3-基）苯氧基）-甲基）喹啉（[11C]MP-10）进行放射性标记。MP-10是一种高效的PDE10A抑制剂（IC50 = 0.37 nM），对PDE10A与其他PDEs和CNS受体具有高选择性（1000倍）。我们还成功地修饰了MP-10的结构，制成了氟类似物TuJF103 （IC50 = 0.27 nM）。[11C]MP-10和[18F]TUJF103在大鼠体内的初步生物分布评估，以及这两种放射性示踪剂在猴子体内的显微pet成像研究显示，靶区（纹状体）和参比区（小脑）之间存在良好的对比。然而，纹状体和小脑的时间-活性曲线分析以及随后对大鼠大脑和血液的代谢物分析表明，在大脑中存在非特异性积累的亲脂性放射性标记代谢物。这些代谢物可能会限制[11C]MP-10或[18F]TUJF103作为新型PET示踪剂成像PDE10A的临床应用。为了克服这些顾虑，本课题将优化MP-10的结构，合成对PDE10A具有高亲和力和选择性的新型类似物；用C-11或F-18对候选铅进行放射性标记，然后使用体内方法验证最佳PET放射性示踪剂对脑内PDE10A成像。因此，R21组分的具体目标包括：(1)通过对MP-10的结构优化合成新的类似物；(2)测定新类似物的体外亲和力；(3)用C-11或F-18对高亲和度（IC50<15 nM）和高选择性（bbb100倍）的配体进行放射性标记；(4)进行放射性示踪剂在大鼠体内的生物分布和脑吸收研究，以确定至少两种有希望的候选物。R33组分的具体目的将是在灵长类动物中继续评估这些候选放射性示踪剂，目的是确定一种PET示踪剂，适用于用PET成像脑内PDE10A的转化临床评估。

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.