Radiolabled MAO-B Substrates for Imaging

描述（由申请方提供）：本项目旨在开发人脑中单胺氧化酶-B（MAO- B）的新放射性标记底物。 在脑中，MAO-B在星形胶质细胞中显著表达，并且增加的MAO-B酶活性已在诸如难治性癫痫、阿尔茨海默病、肌萎缩性侧索硬化和其他神经退行性病症的疾病的许多研究中用作神经胶质增生的生物标志物。 由于反应性神经胶质增生是对脑的各种损伤的局部细胞反应的公认病理标志物，因此神经胶质增生的程度和模式的非侵入性测量可广泛适用于损伤或患病组织（例如，用于癫痫切除术）、相关疾病（阿尔茨海默病与额颞叶痴呆（FTD）或路易体病）的鉴别以及新治疗方法的评价，因此可以显著帮助许多CNS疾病的诊断和管理。 该项目提出了新的碳-11和氟-18标记底物的设计、化学和放射化学合成以及体外和体内评价，用于MAO-B酶活性的正电子发射断层扫描（PET）成像。 在MAO-B成像的创新方法中，该项目将制备4-噻吩基-和4-氨基甲酰基-N-甲基-1，2，3，6-二氢吡啶的新型放射性标记衍生物，已知这些衍生物是无毒的MAO-B底物，可形成极性反应产物。 4-噻吩基-1，2，3，6-二氢吡啶氧化为相应的无毒二氢吡啶鎓盐; 4-氨基甲酰基-1，2，3，6-二氢吡啶氧化为相应的二氢吡啶鎓盐，其自发水解释放极性胺。 来自MAO-B酶促氧化的极性放射性标记产物将在酶作用位点累积，因此使用代谢捕获的概念来提供可量化的PET成像数据。 将使用离体解剖技术评价候选放射性示踪剂与MAO- B的体外反应性（Km和kcat）以及啮齿动物体内良好的脑摄取和保留。 然后将通过microPET成像评价有前途的放射性示踪剂在恒河猴脑中的脑摄取、不可逆捕获和总体药代动力学。 该项目的总体目标是确定适当的放射性标记底物，可以进一步评估和验证在人体PET成像中的应用。

DESCRIPTION (provided by applicant): This project aims to develop new radiolabeled substrates for the enzyme monoamine oxidase-B (MAO- B) in the human brain. In the brain, MAO-B is conspicuously expressed in astrocytes, and increased MAO-B enzymatic activity has been used as a biomarker of gliosis in numerous studies of diseases such as refractory epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, and other neurodegenerative conditions. As reactive gliosis is a recognized pathological marker of localized cellular responses to a wide variety of insults to the brain, non-invasive measurement of the extent and pattern of gliosis could have wide applicability to the localization of injured or diseased tissue (e.g., for resection in epilepsy), differentiation of related diseases (Alzheimer's versus frontal-temporal dementia (FTD) or Lewy Body disease), and evaluation of new therapeutic treatments, and thus could significantly assist in the diagnosis and management of many CNS diseases. This project proposes the design, chemical and radiochemical synthesis, and evaluation in vitro and in vivo of new carbon-11 and fluorine-18 labeled substrates for Positron Emission Tomography (PET) imaging of MAO-B enzymatic activity. In an innovative approach to MAO-B imaging, the project will prepare novel radiolabeled derivatives of 4-thiophenyl- and 4-carbamoyl-N-methyl-1,2,3,6-dihydropyridines that are known to be non-toxic MAO-B substrates that form polar reaction products. 4-Thiophenyl-1,2,3,6-dihydropyridines are oxidized to the corresponding non-toxic dihydropyridinium salts; the 4-carbamoyl-1,2,3,6- dihydropyridines are oxidized to the corresponding dihydropyridinium salts that spontaneously hydrolyze to release polar amines. The polar radiolabeled products from MAO-B enzymatic oxidation will accumulate at the site of enzyme action, thus using the concept of metabolic trapping to provide quantifiable PET imaging data. Candidate radiotracers will be evaluated for in vitro reactivity with MAO- B (Km and kcat) and good in vivo brain uptake and retention in rodents using ex vivo dissection techniques. Promising radiotracers will then be evaluated for brain uptake, irreversible trapping, and overall pharmacokinetics in rhesus monkey brain by microPET imaging. The overall goal of the project is to identify appropriate radiolabeled substrates that can be further evaluated and validated for applications in human PET imaging.