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.

概括阿尔茨海默氏病（AD）是痴呆症的最常见形式，也是65岁以上成人的主要死亡原因。不幸的是，早期诊断和治疗发展的进步受到了匮乏敏感的生物标志物可以检测早期，功能相关的，神经分子的变化：尽管数据从基因组广泛的关联研究中揭示了与健康先天免疫功能丧失有关的基因作为AD的主要危险因素，仍然需要生物标志物研究神经免疫功能在这种疾病的发展和发展期间。正电子发射断层扫描（PET）是极其的敏感的分子成像模态非常适合研究此类生物标志物，并建立了非效用生化过程的体内询问。现有的神经炎症的宠物生物标志物（例如易位蛋白18 kDa [TSPO]，CB2，CSF1R，P2X7）遭受重大缺点，包括较差中枢神经系统（CNS）中多种细胞类型的阐明功能和/或表达。在CNS中，腺苷二磷酸受体P2Y12R仅在小胶质细胞上表达中枢神经系统的免疫效应细胞，并驱动趋化性和与小胶质细胞相关的形态变化激活。普遍认为是稳态小胶质细胞的生物标志物，P2Y12表达一直是证明急性（例如脂多糖挑战）和慢性（例如AD）的急性减少神经炎症。来自高级AD患者的后人类脑组织表现出全球性降低P2Y12R表达和在周围的小胶质细胞上几乎完全不存在P2Y12R表达淀粉样蛋白斑块。尽管药理学目标非常出色，但目前仍有无CNS-PENETION P2Y12R PET示踪剂。为了满足这种未满足的需求，我确定了临床药物的候选者 AZD1283作为可承诺的宠物示踪剂。最近，我设计了一种radiolabel的策略碳11（T1/2 = 20.4分钟），合成[11C] AZD1283，表明它在人血浆中的体外非常稳定。在这里，我将[11C] AZD1283与TSPO PET示踪剂[11C] DPA-713进行比较，以测量其测量更改的能力在两个鼠神经炎症模型中的小胶质细胞中（AIM 1）。此外，我将评估翻译 [11C] AZD1283通过成像健康的非人类灵长类动物和人类体外自显影术的潜力广告脑组织（AIM 2）。通过追求这些目标获得的经验将使我直接发展技能适用于未来的独立研究开发针对免疫系统的示踪剂和疗法。我会在米歇尔·詹姆斯（Michelle James）的心态下进行这项工作斯坦福大学病理学主席Thomas Montine，医学博士Thomas Montine的额外精神训练。他们的精神训练与我在斯坦福大学提供的优质培训环境和资源相结合，非常高导电以成功完成该项目，并最终将成功过渡到职业作为创新和有效的独立物理科学家。