Radiolabled MAO-B Substrates for Imaging

用于成像的放射性标记 MAO-B 底物

• 批准号: 8296467
• 负责人: MICHAEL R KILBOURN
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296467
• 关键词: Address; Alzheimer' s Disease; Amines; Amino Acids; Amyotrophic Lateral Sclerosis; Applications Grants; Astrocytes; Biological Markers; Brain; Bromides; Carbon; Central Nervous System Diseases; Cerebrum; Chemicals; Data; Degenerative Disorder; Dementia; Development; Diagnosis; Diagnostic; Diet; Dihydropyridines; Disease; Dissection; Drug Kinetics; Enzymes; Epilepsy; Evaluation; Excision; Fluorine; Future; Gliosis; Goals; Human; Image; In Vitro; Injury; Label; Lewy Body Disease; Location; Macaca mulatta; Measurement; Measures; Metabolic; Metabolism; Monoamine Oxidase B; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pattern; Peripheral; Pharmaceutical Preparations; Positron-Emission Tomography; Pre-Clinical Model; Primates; Protein Biosynthesis; Radioactivity; Radiolabeled; Radiopharmaceuticals; Reaction; Recovery; Refractory; Rodent; Salts; Site; Techniques; Time; Tissues; Toxic effect; analog; brain tissue; chemical synthesis; design; dihydropyridine; dosimetry; enzyme activity; enzyme substrate; human disease; in vivo; inhibitor/antagonist; injured; innovation; meetings; methyl iodide; novel; novel therapeutics; oxidation; pharmacokinetic model; radiochemical; radiotracer; reaction rate; response; suicide inhibitor; uptake

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.

描述(申请人提供)：该项目旨在为人脑中的单胺氧化酶-B(MAO-B)酶开发新的放射性标记底物。在大脑中，MAO-B在星形胶质细胞中显著表达，MAO-B酶活性的增加已被用作胶质增生的生物标志物，用于许多疾病的研究，如难治性癫痫、阿尔茨海默病、肌萎缩侧索硬化症和其他神经退行性疾病。由于反应性胶质细胞增生症是公认的局部细胞对各种对脑的侮辱反应的病理标志，对胶质细胞增殖性程度和模式的非侵入性测量可广泛应用于损伤或病变组织的定位(例如，癫痫的切除)、相关疾病的鉴别(阿尔茨海默病与额叶-颞叶痴呆(FTD)或路易体病)以及新的治疗方法的评估，从而可能显著有助于许多中枢神经系统疾病的诊断和治疗。本项目提出了用于正电子发射断层扫描(PET)MAO-B酶活性成像的新型碳-11和氟-18标记底物的设计、化学和放射化学合成以及体内外评价。在MAO-B成像的一种创新方法中，该项目将制备新型的4-硫苯基和4-氨基甲酰基-N-甲基-1，2，3，6-二氢吡啶的放射性标记衍生物，已知这些衍生物是无毒的MAO-B底物，形成极性反应产物。4-硫苯基-1，2，3，6-二氢吡啶被氧化成相应的无毒的二氢吡啶盐；4-氨基甲酰基-1，2，3，6-二氢吡啶被氧化成相应的二氢吡啶盐，这些二氢吡啶盐自发水解释放出极性胺。MAO-B酶氧化产生的极性放射性标记产物会聚集在酶作用的部位，从而利用代谢捕捉的概念来提供可量化的PET成像数据。将使用体外解剖技术评估候选放射性示踪剂与MAO-B(KM和KCAT)的体外反应性以及啮齿类动物良好的体内脑摄取和保持能力。有希望的放射性示踪剂将通过microPET成像对猕猴脑内的脑摄取、不可逆捕获和总体药代动力学进行评估。该项目的总体目标是确定适当的放射性标记底物，这些底物可以进一步评估和验证在人类PET成像中的应用。