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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' 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

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.

总结 阿尔茨海默病（AD）是痴呆症的最常见形式，并且是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展受到缺乏的阻碍。 敏感的生物标志物能够检测早期，功能相关的神经分子变化：虽然数据 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 在这种疾病的发展过程中和发展过程中。正电子发射断层扫描（PET）是一种非常有效的 灵敏的分子成像模式非常适合研究这种生物标志物，具有非生物标志物的既定效用。 生物化学过程的侵入性体内询问。神经炎症的现有PET生物标志物（例如，的 转运蛋白18 kDa [TSPO]、CB 2、CSF 1 R、P2 X7）具有显著的缺点，包括差的 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CNS内，腺苷二磷酸受体P2 Y12 R仅在小胶质细胞上表达，小胶质细胞是先天性的神经胶质细胞。 CNS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学变化。 activation.通常认为P2 Y12表达是稳态小胶质细胞的生物标志物， 证明在急性（例如，脂多糖攻击）和慢性（例如，广告） 神经炎症晚期AD患者的尸检人脑组织显示出全球性的 P2 Y12 R表达减少，周围小胶质细胞上几乎完全没有P2 Y12 R表达。 β淀粉样斑块尽管是一个非常好的表征药理学靶点，但目前 没有CNS可穿透的P2 Y12 R 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， AZD 1283是一种很有前途的PET示踪剂。最近，我设计了一种策略，用放射性标记这种分子， 碳-11（t1/2=20.4 min），合成了[11 C] AZD 1283，并显示其在体外人血浆中高度稳定。 在此，我将比较[11 C] AZD 1283与TSPO PET示踪剂[11 C]DPA-713测量改变的能力 在两种神经炎症的鼠模型中的小胶质细胞中（目的1）。此外，我将评估翻译 [11 C] AZD 1283通过健康非人灵长类动物成像和人体体外放射自显影的潜力 AD脑组织（Aim 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 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。我会 在Michelle James博士的指导下进行这项工作，Michelle James博士是神经炎症PET的世界专家， 来自斯坦福大学病理学系主任托马斯·蒙廷（医学博士、博士）的额外指导。他们的指导，在 再加上斯坦福大学提供给我的优秀培训环境和资源， 有利于顺利完成这个项目，并最终使成功过渡到职业生涯 作为一个创新和有效的独立医生科学家。