NOVEL PET TRACERS FOR IMAGING OF ALZHEIMER'S DISEASE

用于阿尔茨海默病成像的新型宠物示踪剂

• 批准号: 9058975
• 负责人: Vijay Sharma
• 金额: $ 31.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058975
• 关键词: Affinity; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Autopsy; Binding; Binding Sites; Biochemical; Biodistribution; Biological; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Carotid Artery Ulcerating Plaque; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrum; Characteristics; Clinical; Cognitive; Competitive Binding; Coupled; Critiques; Data; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic; Diffuse; Discipline of Nuclear Medicine; Disease; Disease Management; Drug Kinetics; Early Diagnosis; Elderly; Evaluation; Event; FDA approved; FVB Mouse; Functional disorder; Generations; Goals; Health; Hippocampus (Brain); Human; Image; Image Analysis; Imaging Techniques; Impaired cognition; In Vitro; Injection of therapeutic agent; Investigation; Label; Lead; Lesion; Life; Magnetic Resonance Imaging; Metabolism; Microscopy; Modeling; Molecular; Molecular Target; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parkinson Disease; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Prions; Process; Radiopharmaceuticals; Reporting; Resources; Senile Plaques; Serum; Signal Transduction; Site; Specificity; Specimen; Staging; Stratification; Symptoms; Synapses; Tail; Text; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Toxicology; Tracer; Transgenic Mice; Treatment Efficacy; Validation; Variant; Veins; X-Ray Computed Tomography; amyloid formation; analog; arm; brain parenchyma; brain tissue; cerebrovascular amyloid; cross reactivity; density; design; dosimetry; frontal lobe; human tissue; imaging agent; in vivo; microPET; microPET/CT; molecular imaging; neuron loss; non-demented; non-invasive imaging; nonhuman primate; noninvasive diagnosis; normal aging; novel; protein biomarkers; radiotracer; response; single photon emission computed tomography; targeted agent; tau Proteins; two-photon; uptake; white matter

 DESCRIPTION (provided by applicant): Several lines of investigations indicate that amyloid formation precedes decades prior to beginning of neurodegeneration phase, and the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs) in nondemented older adults could represent an earlier manifestation of AD prior to its clinical expression. To further embellish diagnostic nuclear medicine imaging resources, 18F-Avid-45,18F-Flutemetamol, and 18F-Florbetaben have recently gained FDA approval for Aβ imaging. Among these agents, 11C-PIB continues to be the most thoroughly investigated PET radiopharmaceutical for Aβ imaging. Recent reports indicate that 11C-PIB could not detect cerebral Aβ in a patient confirmed via clinical, cognitive, and cerebrospinal fluid biomarkers of AD, thus raising further concerns for sensitivity of PIB and other agents to detect AD variants characterized predominantly by diffuse Aβ plaques. Additionally, recent clinicopathological studies of PD patients have also indicated limitations of PIB imaging to differentiate PD patients with or without dementia, despite the presence of abundant Aβ in brains of those patients. To further supplement armamentarium of promising PET Aβ imaging agents, an easily accessible, efficient, highly specific 18F-PET agent and potentially capable of binding to both fibrillar and diffuse plaques, including the more dense sites on Aβ to enable high sensitivity for detection (at prodromal stages of the disease) would be highly desirable, and continues to be an unmet goal. To accomplish this objective, we have rationally designed a novel heterocyclic fluorescent molecule (18F-AI-187) from an entirely a new class of molecules that shows concentration dependent and saturable binding, with Kd values of 1.4±0.35nM and 2.9 ±1.35nM, to AD homogenates and preformed Aβ1-42 fibrils, respectively, the unlabeled fluorescent counterpart detects both fibrillar plaques and displays cerebral amyloid angiopathy (CAA) ex vivo in the hippocampus regions of brain sections in APPsw+/-/PS1 mice and also detects diffuse plaques, compact plaques, and vascular deposits (CAA) in human tissues. Further, the PET tracer 18F-AI-187 demonstrates an extremely high first pass extraction in brains (8.86 ± 0.32 %ID/g %ID/g; 2 min post tail-vein injection) of FVB mice, and followed by a washout (25% faster than 18F-Avid 45) in absence of targeted plaques. Compared with11C-PIB, 18F-Flutemetamol (metabolizes faster than 11C-PIB), and 18F-Avid45 that undergo facile metabolism in vivo, 18F-AI-187 remains non-metabolized in human serum. Therefore, the high first pass extraction into brains coupled with faster clearance from the blood pool and lack of metabolites offer critical characteristics that could enhance overall signal to background ratios and target specificity to assist image analysis. Preliminary multiphoton microscopy in live APPsw+/-/PS1 (15 months old) mice demonstrates that F-AI- 187 traverses blood brain barrier to instantaneously labels plaques in brain parenchyma and blood vessels (CAA), and plaques remain labeled for investigated time points. Preliminary, microPET/CT imaging shows higher brain uptake of the radiotracer (30 min post-tail-vein injection), and its retention in the cortex of transgenic mice compared with their age-matched Bl6 counterparts, consistent with the binding of the tracer to Aβ plaques. Finally and importantly, the agent is als highly specific for AD (displays no cross-reactivity with biomarkers of other neurodegenerative diseases); while also detecting diffuse and compact plaques in a PIB- Aβ+ AD case. Armed with this highly provocative data on our lead agent, now we propose to: 1) Perform complete pharmacokinetic analysis of 18F-AI-187 or the second generation of lead agents to determine their translational potential to serve as noninvasive Aβ-targeted probes in age-matched APPsw+/- transgenic mice (target specificity), WT counterparts (controls), and nonhuman primates (baseline SNR analysis) via evaluation of time-activity curves (TACs), using either microPET/CT or microPET/MR or PET/MR imaging, perform arterial metabolite analysis and dosimetry studies to identify highly specific imaging agents to advance translational leads into non-GMP-toxicology studies for eIND filing; 2) Perform focused SAR studies to develop second generation of novel heterocyclic molecules capable of detecting Aβ plaques in early stages of AD prior to its clinical expression. 3) Perform complete biochemical characterization of second generation Aβ-targeted agents via multiple binding and competitive displacement assays for evaluation of targeted sites on Aβ, assess BBB permeability and ability to label plaques in parenchyma via biodistribution studies and 2-photon imaging, phosphorimaging studies in vitro, perform ex vivo binding studies of AD brain homogenates and human AD brain tissue sections, including specificity for Aβ compared with other biomarker proteins (tau, prion, TDP43,and α-synclein) prevalent in other neurodegenerative diseases for determining target selectivity of second generation agents. Upon further biochemical validation, these novel molecular imaging agents could enable noninvasive PET interrogation of Aβ in patients at prodromal stages of AD, better guide stratification of AD patients from those of other neurodegenerative diseases, and assist analysis of the efficacy for new molecular-targeted disease-modifying therapies, thus overall assisting management of AD.

 描述（由申请人提供）：多项研究表明，淀粉样蛋白的形成早于神经变性阶段开始的数十年，并且非痴呆老年人中老年斑 (SP) 和神经原纤维缠结 (NFT) 的存在可能代表 AD 的早期表现在其临床表达之前进一步完善诊断核医学成像资源，18F-Avid-45，18F-Frudemetamol和18F-Florbetaben 最近获得 FDA 批准用于 Aβ 成像，在这些药物中，11C-PIB 仍然是研究最彻底的用于 Aβ 成像的 PET 放射性药物。最近的报告表明，11C-PIB 无法检测经临床证实的患者的脑部 Aβ。 AD 的认知和脑脊液生物标志物，因此引起了人们对 PIB 和其他药物检测 AD 变异（进一步优先以弥漫性 Aβ 斑块为特征）的敏感性的担忧。 PD 患者的临床病理学研究还表明，PIB 成像在区分患有或不患有痴呆的 PD 患者方面存在局限性，尽管这些患者的大脑中存在丰富的 Aβ。高度特异性的 18F-PET 试剂，并且可能能够结合纤维状和弥漫性斑块，包括 Aβ 上更密集的位点，以实现高灵敏度检测（在疾病的前驱阶段） 为了实现这一目标，我们从一类全新的分子中合理地设计了一种新型杂环荧光分子（18F-AI-187），该分子显示出浓度依赖性和可饱和结合，具有 Kd 值。​​对于 AD 匀浆和预先形成的 Aβ1-42 原纤维分别具有 1.4±0.35nM 和 2.9 ±1.35nM，未标记的荧光对应物可检测两者PET 示踪剂可在 APPsw+/-/PS1 小鼠脑切片的海马区域中离体显示纤维状斑块并显示脑淀粉样血管病 (CAA)，还可以检测人体组织中的弥漫性斑块、致密斑块和血管沉积物 (CAA)。 18F-AI-187 在大脑中表现出极高的首过提取率（8.86 ± 0.32 %ID/g %ID/g；2 分钟与 11C-PIB、18F-Frudemetamol（比 11C-PIB 代谢更快）和 18F 相比，对 FVB 小鼠进行尾静脉注射后进行洗脱（比 18F-Avid 45 快 25%）。 -Avid45 在体内容易代谢，18F-AI-187 在人体中保持非代谢因此，大脑中的高首过提取率以及从血池中更快的清除率和缺乏代谢物提供了可以增强整体信号与背景比和目标特异性的关键特征，以协助实时 APPsw+/- 中的初步多光子显微镜分析。 /PS1（15 个月大）小鼠证明 F-AI-187 穿过血脑屏障，立即标记脑实质和血管 (CAA) 中的斑块，并且斑块保留下来初步的 microPET/CT 成像显示，与年龄匹配的 Bl6 骨骼相比，转基因小鼠的大脑对放射性示踪剂的吸收更高（尾静脉注射后 30 分钟），并且其在皮质中的保留率更高。最后也是重要的是，该试剂对 AD 具有高度特异性（与其他神经退行性疾病的生物标志物没有交叉反应），同时还可以检测弥漫性和致密性斑块。在 PIB-Aβ+ AD 案例中，有了关于我们的主要代理人的高度挑衅性的数据，现在我们建议： 1) 对 18F-AI-187 或第二代先导药物进行完整的药代动力学分析，以确定其在年龄匹配的 APPsw+/- 转基因小鼠（目标特异性）、WT 克（对照）中作为非侵入性 Aβ 靶向探针的转化潜力）和非人类灵长类动物（基线 SNR 分析），通过使用 microPET/CT 或 microPET/MR 或 PET/MR 评估时间活动曲线 (TAC)成像，进行动脉代谢物分析和剂量测定研究，以确定高度特异性的显像剂，以将转化线索推进到非 GMP 毒理学研究中，以进行 eIND 备案；2) 进行重点 SAR 研究，开发能够检测 Aβ 斑块的第二代新型杂环分子。 3) 通过多重结合和竞争性置换测定对第二代 Aβ 靶向药物进行完整的生化表征，以评估 Aβ 的靶向位点、评估 BBB 通透性和能够通过生物分布研究和 2 光子成像、体外磷成像研究来标记实质中的斑块，执行 AD 脑匀浆和人 AD 脑组织切片的离体结合研究，包括与其他神经退行性疾病中普遍存在的其他生物标志物蛋白（tau、朊病毒、TDP43 和 α-synclein）相比 Aβ 的特异性，以确定第二代药物的靶点选择性。经过进一步的生化验证，这些新型分子成像剂可以对 AD 前驱阶段患者的 Aβ 进行无创 PET 检查，更好地指导 AD 患者与其他神经退行性疾病患者的分层，并协助分析新的分子靶向疾病缓解疗法的功效，从而全面协助 AD 的管理。