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（由申请方提供）：多项研究表明，淀粉样蛋白的形成早于神经退行性变阶段开始前数十年，非痴呆老年人中老年斑（SP）和神经纤维缠结（NFT）的存在可能代表AD在临床表现之前的早期表现。为了进一步丰富诊断核医学成像资源，18F-Avid-45、18F-Flutemetalone和18F-Florbetaben最近获得了FDA批准用于Aβ成像。在这些药物中，11 C-PIB仍然是研究最彻底的PET放射性药物，用于Aβ成像。最近的报告表明，11 C-PIB无法检测经临床、认知和脑脊液AD生物标志物证实的患者的脑Aβ，因此进一步关注PIB和其他药物检测主要以弥漫性Aβ斑块为特征的AD变体的灵敏度。此外，最近对PD患者的临床病理学研究也表明，尽管这些患者的脑中存在丰富的Aβ，但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。为了进一步补充有前景的PET Aβ显像剂的设备，将开发一种容易获得的、有效的、高度特异性的18F-PET剂，并且该18F-PET剂可能能够结合纤维状斑块和弥漫性斑块，包括Aβ上更密集的位点，以实现检测的高灵敏度（在疾病的前驱期）。 这是非常可取的，仍然是一个未实现的目标。为了实现这一目标，我们合理设计了一种新型杂环荧光分子，（18 F-AI-187）来自一类全新的分子，其显示出与AD匀浆和预形成的Aβ1-42原纤维的浓度依赖性和饱和结合，Kd值分别为1.4± 0.35 nM和2.9 ± 1.35 nM，未标记的荧光对应物在APPsw+/-/PS1小鼠脑切片的海马区中检测纤维斑并显示离体脑淀粉样血管病（CAA），并且还检测弥散斑，致密斑，和人体组织中的血管沉积物（CAA）。此外，PET示踪剂18F-AI-187在FVB小鼠的脑中显示出极高的首过提取（8.86 ± 0.32%ID/g %ID/g;尾静脉注射后2分钟），随后在不存在靶向斑块的情况下进行洗脱（比18F-Avid 45快25%）。与体内易于代谢的11 C-PIB、18F-Flutemetetaline（代谢速度快于11 C-PIB）和18F-Avid 45相比，18F-AI-187在人血清中保持非代谢状态。因此，脑内的高首过提取加上从血池中的更快清除以及代谢物的缺乏提供了关键特征，其可以增强总体信号与背景比和目标特异性，以辅助图像分析。在活的APPsw+/-/PS1（15个月大）小鼠中的初步多光子显微镜检查表明，F-AI- 187穿过血脑屏障以瞬时标记脑实质和血管（CAA）中的斑块，并且斑块在研究的时间点保持标记。初步的microPET/CT成像显示，与其年龄匹配的B16对应小鼠相比，转基因小鼠的放射性示踪剂的脑摄取（尾静脉注射后30分钟）更高，并且其在皮质中的保留更高，这与示踪剂与Aβ斑块的结合一致。最后且重要的是，该试剂对AD也具有高度特异性（与其他神经退行性疾病的生物标志物不显示交叉反应性）;同时还检测PIB-A β+ AD病例中的弥漫性和致密斑块。有了这些关于我们主要代理人的高度挑衅性数据，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+/-转基因小鼠中作为非侵入性Aβ靶向探针的翻译潜力（靶标特异性），WT对应物（对照）和非人灵长类动物（基线SNR分析）通过使用microPET/CT或microPET/MR或PET/MR成像评价时间-活动曲线（TAC），进行动脉代谢物分析和剂量测定研究，以识别高度特异性的显像剂，从而将潜在药物转化为非GMP毒理学研究，以便进行eIND申报;（二）进行集中的SAR研究，以开发第二代新型杂环分子，能够在AD早期阶段检测Aβ斑块，临床表现3)通过多种结合和竞争性置换试验对第二代Aβ靶向药物进行完整的生物化学表征，以评价Aβ上的靶向位点，通过生物分布研究和双光子成像评估BBB渗透性和标记实质中斑块的能力，体外磷酸成像研究， 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常见的其他生物标志物蛋白（tau、朊病毒、TDP 43和α-synclein）相比的Aβ特异性，以确定第二代药物的靶向选择性。在进一步的生化验证后，这些新型分子成像剂可以在AD前驱期患者中实现Aβ的无创PET询问，更好地指导AD患者与其他神经退行性疾病患者的分层，并辅助分析新的分子靶向疾病修饰疗法的疗效，从而全面辅助AD的管理。