A new P2Y12R PET radioligand for measuring microglial function in Alzheimer's disease

一种新的 P2Y12R PET 放射性配体，用于测量阿尔茨海默病中的小胶质细胞功能

• 批准号: 10355306
• 负责人: Michelle Louise James
• 金额: $ 43.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355306
• 关键词: AD transgenic mice; Acute; Adenosine Diphosphate; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Anti-Inflammatory Agents; Autopsy; Autoradiography; Behavior; Binding; Binding Proteins; Biochemical Process; Biodistribution; Biological Markers; Brain; Cause of Death; Cells; Chemotaxis; Chronic; Clinical Trials; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Effector Cell; Elderly; FDA approved; Functional Imaging; Functional disorder; Genes; Goals; Human; Image; Image Analysis; Immune; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Innate Immune System; Kinetics; Lipopolysaccharides; Measures; Metabolic; Microglia; Modeling; Molecular; Monitor; Morphology; Mus; Myelogenous; Myeloid Cells; Neuraxis; Neuroimmune; Pathogenesis; Pathology; Patient-Focused Outcomes; Pharmacology; Phenotype; Plasma Proteins; Positron-Emission Tomography; Process; Production; Proteins; Radiochemistry; Radiolabeled; Research; Risk Factors; Rodent; Role; Senile Plaques; Signal Transduction; Specificity; Therapeutic; Time; Tissues; Tracer; Transgenic Mice; Translations; United States; Visualization; antagonist; base; brain cell; brain tissue; cell type; clinical translation; genome wide association study; imaging approach; imaging biomarker; imaging modality; immune activation; immunohistochemical markers; immunomodulatory therapies; improved; in vivo; in vivo imaging; individual patient; innate immune function; lipophilicity; molecular imaging; mouse model; neuroinflammation; novel; novel therapeutics; radioligand; radiotracer; receptor; sex; spatiotemporal; tau Proteins; therapy outcome; tool; uptake

SUMMARY Alzheimer's disease (AD) is the most common form of dementia in older adults and the 6th leading cause of death in the United States. Unfortunately, there are currently no FDA approved disease-modifying therapeutics available for AD, and definitive diagnosis is only possible via postmortem analysis. The limited number of sensitive biomarkers enabling detection of early, functionally relevant, neuromolecular changes in AD is a major impediment to improving diagnosis and validating novel therapeutics. Although data from genome wide association studies and immunohistochemistry have implicated neuroinflammation and a loss of healthy innate immune function as major AD risk factors, biomarkers to investigate neuro-immune function preceding and during AD remain extremely limited. Positron Emission Tomography (PET) is an highly sensitive molecular imaging modality well suited to studying such biomarkers longitudinally, with established utility for non-invasive in vivo interrogation of biochemical processes. Existing PET imaging biomarkers of neuroinflammation (e.g., the translocator protein 18 kDa [TSPO]) suffer from significant drawbacks, including a poorly elucidated functional role and/or expression across multiple cell types in the central nervous system (CNS), which complicates image analysis. Within the CNS, adenosine diphosphate receptor (P2Y12R) expression is restricted to microglia, the innate immune effector cells of the brain. Generally considered a biomarker of homeostatic microglia, P2Y12R expression drives chemotaxis and activation-associated morphological changes. Importantly, P2Y12R expression decreases in both acute and chronic neuroinflammation, as shown in rodents after lipopolysaccharide challenge and in AD transgenic mice. Moreover, postmortem human brain tissue from advanced AD patients demonstrated global reduction in P2Y12R expression, with a near total absence on microglia surrounding amyloid-beta plaques. While P2Y12R is an extremely well characterized pharmacological target, there are currently no CNS-penetrable PET radiotracers for this biomarker. We have identified the P2Y12R antagonist AZD1283 as a promising potential PET tracer based on its high affinity and favorable lipophilicity (measured LogD 2.8) indicative of its high likelihood for CNS uptake. Upon optimization of the cyanation radiochemistry outlined herein, we propose to assess the in vivo kinetics, biodistribution, stability, and specificity of [11C]AZD1283 in healthy mice, as well as the ability of [11C]AZD1283 to detect alterations in P2Y12R expression in human AD postmortem tissue using autoradiography (Aim 1). Additionally, we will interrogate the dynamics of microglial P2Y12R expression in two murine models of acute and chronic neuroinflammation (Aim 2). Completion of these aims will result in development and characterization of the first P2Y12R PET tracer suitable for in vivo PET imaging, with high potential for clinical translation. Ultimately, such a tool could serve as an endpoint in clinical trials of novel AD immunomodulatory therapies, in addition to helping monitor disease progression in individual patients.

摘要 阿尔茨海默病(AD)是老年人最常见的痴呆症形式，是老年痴呆症的第六大病因 美国的死亡案例。不幸的是，目前还没有FDA批准的疾病修正疗法 适用于阿尔茨海默病，只有通过尸检分析才能做出明确的诊断。数量有限的 敏感的生物标志物能够检测AD的早期、功能相关的神经分子变化是一个主要的 阻碍改进诊断和验证新的治疗方法。尽管来自全基因组的数据 关联性研究和免疫组织化学研究表明神经炎症和健康先天缺陷的丧失。 免疫功能是AD的主要危险因素，是研究神经免疫功能的生物标志物 在AD期间仍然极其有限。正电子发射断层扫描(PET)是一种高度敏感的分子 成像模式非常适合于纵向研究这种生物标志物，具有公认的非侵入性实用价值 生物化学过程的活体讯问。现有的神经炎症的PET成像生物标志物(例如， 转位蛋白18 kDa[TSPO])具有明显的缺陷，包括功能不明确 中枢神经系统(CNS)中多种细胞类型的角色和/或表达，使图像复杂化 分析。在中枢神经系统内，二磷酸腺苷受体(P2Y12R)的表达仅限于小胶质细胞， 大脑的先天免疫效应细胞。被普遍认为是动态平衡小胶质细胞的生物标记物，P2Y12R 表达驱动趋化性和激活相关的形态变化。重要的是，P2Y12R 在急性和慢性神经炎中，表达减少，如在啮齿动物内毒素后所示 攻击和在AD转基因小鼠中。此外，晚期AD患者的死后人脑组织 显示出P2Y12R表达的全局性减少，周围的小胶质细胞几乎完全缺失 淀粉样β斑块。虽然P2Y12R是一个非常有特点的药理靶点，但有 目前还没有这种生物标志物的中枢神经系统可穿透的PET放射性示踪剂。我们已经确定了P2Y12R拮抗剂 AZD1283具有很高的亲和力和良好的亲脂性，是一种很有前途的PET示踪剂(测量 LogD 2.8)表明其摄取中枢神经系统的可能性很高。关于氰化放射化学的优化 在此概述，我们建议评估体内动力学，生物分布，稳定性和特异性 [11C]AZD1283在健康小鼠中的表达，以及[11C]AZD1283检测P2Y12R表达变化的能力 在人类阿尔茨海默病死后组织中使用放射自显影(目标1)。此外，我们还将审问 小胶质细胞P2Y12R在两种急性和慢性神经炎小鼠模型中的表达(目标2)。完成 这些目标将导致开发和表征第一个适用于体内的P2Y12R PET示踪剂 PET成像，具有很高的临床翻译潜力。最终，这样的工具可以作为 除了帮助监测疾病进展外，新型AD免疫调节疗法的临床试验 个别病人。