Development of a Novel PET Tracer for Imaging Microglial Function in Alzheimer's Disease

开发一种新型 PET 示踪剂，用于对阿尔茨海默氏病的小胶质细胞功能进行成像

基本信息

批准号：
10834001
负责人：
Isaac Mackenzie Jackson
金额：
$ 4.04万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2024-09-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10834001
关键词：
Acute Address Adenosine Diphosphate Adult Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Anti-Inflammatory Agents Autopsy Autoradiography Basic Science Binding Biochemical Process Biological Markers Brain CNR2 gene CSF1R gene Carbon Cause of Death Cells Central Nervous System Chemotaxis Chronic Clinical Data Dementia Development Disease Disease Progression Doctor of Philosophy Early Diagnosis Early treatment Effector Cell Environment Evaluation Fellowship Formulation Functional Imaging Future Genes Goals Human Image Immune Immune system In Vitro Inflammation Inflammatory Knockout Mice Lipopolysaccharides Measures Medicine Mentors Mentorship Microglia Modeling Molecular Monitor Morphology Mus Myeloid Cells Neuroimmune Pathogenesis Pathology Physicians Plasma Positron-Emission Tomography Process Proteins Radiolabeled Research Research Personnel Resources Risk Factors Rodent Role Saimiri Saline Scientist Senile Plaques Specificity Time Tracer Training Transgenic Mice Visualization Work brain cell brain tissue career cell type clinical translation drug candidate experience genome wide association study glial activation human disease human model human tissue imaging approach imaging modality imaging study immune activation immunomodulatory therapies in vivo innate immune function innovation molecular imaging mouse model neuroinflammation nonhuman primate novel pharmacologic radiotracer receptor research study skills spatiotemporal species difference specific biomarkers targeted treatment tau Proteins therapy development tool translational potential uptake

项目摘要

SUMMARY Alzheimer’s disease (AD) is the most common form of dementia and a major cause of death in adults over 65. Unfortunately, advancements in early diagnosis and treatment development have been hindered by a paucity of sensitive biomarkers enabling detection of early, functionally relevant, neuromolecular changes: Although data from genome wide association studies have revealed genes relating to a loss of healthy innate immune function as a major risk factor for AD, there remains a need for biomarkers to investigate neuro-immune function preceding and during the development of this disease. Positron Emission Tomography (PET) is an extremely sensitive molecular imaging modality well suited to studying such biomarkers, with established utility for non- invasive in vivo interrogation of biochemical processes. Existing PET biomarkers of neuroinflammation (e.g., the translocator protein 18 kDa [TSPO], CB2, CSF1R, P2X7) suffer from significant drawbacks including a poorly elucidated functional role and/or expression across multiple cell types in the central nervous system (CNS). Within the CNS, the adenosine diphosphate receptor P2Y12R is expressed exclusively on microglia, the innate immune effector cells of the CNS, and drives chemotaxis and morphological changes associated with microglial activation. Generally considered a biomarker of homeostatic microglia, P2Y12 expression has been demonstrated to decrease in both acute (e.g., lipopolysaccharide challenge) and chronic (e.g., AD) neuroinflammation. Postmortem human brain tissue from advanced AD patients demonstrated a global reduction in P2Y12R expression and a near total absence of P2Y12R expression on microglia surrounding amyloid-beta plaques. Despite being an extremely well characterized pharmacological target, there are currently no CNS-penetrable P2Y12R PET tracers. Aiming to address this unmet need, I identified clinical drug candidate AZD1283 as a promising possible PET tracer. Recently, I devised a strategy to radiolabel this molecule with carbon-11 (t1/2=20.4 min), synthesized [11C]AZD1283 and showed it to be highly stable in vitro in human plasma. Here, I will compare [11C]AZD1283 with TSPO PET tracer [11C]DPA-713 for their ability to measure alterations in microglia in two murine models of neuroinflammation (Aim 1). Additionally, I will assess the translational potential of [11C]AZD1283 through imaging healthy non-human primates and in vitro autoradiography of human AD brain tissue (Aim 2). The experience gained by pursuing these aims will allow me to develop a skillset directly applicable to future independent research developing tracers and therapies that target the immune system. I will conduct this work under the mentorship of Michelle James, PhD, a world expert in neuroinflammation PET, with additional mentorship from Thomas Montine, MD, PhD, the chair of Pathology at Stanford. Their mentorship, in conjunction with the excellent training environment and resources available to me at Stanford, are highly conducive to successful completion of this project, and will ultimately enable a successful transition to a career as an innovate and effective independent physician scientist.

概括阿尔茨海默病 (AD) 是最常见的痴呆症，也是 65 岁以上成年人死亡的主要原因。不幸的是，早期诊断和治疗开发的进步因缺乏敏感的生物标志物能够检测早期的、功能相关的神经分子变化：尽管数据全基因组关联研究揭示了与健康先天免疫功能丧失相关的基因作为 AD 的主要危险因素，仍然需要生物标志物来研究神经免疫功能在这种疾病发生之前和发生过程中，正电子发射断层扫描 (PET) 是一种极其重要的检查。敏感的分子成像方式非常适合研究此类生物标志物，具有针对非生物标志物的既定实用性神经炎症的现有 PET 生物标志物（例如，易位蛋白 18 kDa [TSPO]、CB2、CSF1R、P2X7）患有明显的斑块，包括不良斑块阐明了中枢神经系统（CNS）中多种细胞类型的功能作用和/或表达。在中枢神经系统内，二磷酸腺苷受体 P2Y12R 仅在小胶质细胞上表达，小胶质细胞是先天的中枢神经系统的免疫效应细胞，并驱动与小胶质细胞相关的趋化性和形态变化 P2Y12 表达通常被认为是小胶质细胞稳态的生物标志物。被证明在急性（例如脂多糖挑战）和慢性（例如 AD）中均有所减少晚期 AD 患者死后的人类脑组织显示出一种全球性的神经炎症。周围小胶质细胞 P2Y12R 表达减少且几乎完全没有 P2Y12R 表达尽管β淀粉样蛋白斑块是一个非常明确的药理学靶标，但目前存在。没有可穿透中枢神经系统的 P2Y12R PET 示踪剂为了解决这一未满足的需求，我确定了临床候选药物。 AZD1283 作为一种很有前景的 PET 示踪剂最近，我设计了一种用放射性标记该分子的策略。 Carbon-11 (t1/2=20.4 min)，合成了[11C]AZD1283，并显示其在体外人血浆中高度稳定。在这里，我将比较 [11C]AZD1283 与 TSPO PET 示踪剂 [11C]DPA-713 测量变化的能力在两种小鼠神经炎症模型的小胶质细胞中（目标 1）。通过健康非人类灵长类动物成像和人类体外放射自显影研究 [11C]AZD1283 的潜力 AD 脑组织（目标 2）。通过追求这些目标获得的经验将使我能够直接发展一套技能。我将适用于未来开发针对免疫系统的示踪剂和疗法的独立研究。这项工作是在神经炎症 PET 领域的世界专家 Michelle James 博士的指导下进行的来自斯坦福大学病理学系主任 Thomas Montine 博士的额外指导。再加上斯坦福大学为我提供的优良的培训环境和资源，我对有利于该项目的成功完成，并最终实现职业生涯的成功过渡作为一名创新且有效的独立医师科学家。