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（由适用提供）：几条研究线表明，淀粉样蛋白在开始神经退行性阶段之前先于淀粉样蛋白的形成，并且在非核心老年人中存在老年斑块（SP）和神经纤维纤维缠结（NFTS）的存在可能代表AD在其临床表达之前的较早表现。为了进一步修饰诊断核医学成像资源，最近获得了18F-Avid-45、18F-氟甲酸和18F氯苯二甲酸酯，最近获得了Aβ成像的FDA批准。在这些药物中，11C-PIB仍然是用于Aβ成像的最彻底研究的PET放射性药物。最近的报道表明，通过AD的临床，认知和脑脊液生物标志物证实，11C-PIB无法检测到患者中的脑Aβ，从而引发了对PIB和其他药物的敏感性的进一步关注，以检测AD AD变体，主要通过弥漫性AβPlaques来主要表征。 PD患者最近的其他临床病理研究还表明，PIB成像以区分有或没有痴呆的PD患者，这些患者的大脑中是否存在丰富的Aβ。为了进一步补充有希望的PETAβ成像剂的武器库，一种易于访问，高效，高度特异的18F-PET剂，并有可能与纤维化和弥漫斑块结合，包括Aβ上更密集的位点，包括在疾病的前驱疾病的前跨阶段，可以启用高敏感性（ 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在AppSW+/ - /ps1小鼠的脑部海马区域中检测纤维斑块并显示脑淀粉样血管病（CAA）在脑切片的海马区域中，并且还检测到人体组织中的弥漫性斑块，紧凑型斑块和血管质量（CAA）。此外，PET示踪剂18F-AI-187在大脑（8.86±0.32％ID/g％ID/G; 2分钟后尾静脉注射后注射）的第一次通过提取极高，然后在吸收靶标plaques的吸收靶标的斑块的情况下进行冲洗（比18F-Avid-avid 45）。与11C-PIB，18F-氟马酚（比11C-PIB的代谢更快）和18F-AVID45在体内经历易于代谢的18F-AVID45，18f-ai-187在人类血清中仍然无代谢。因此，最高的第一通过提取到大脑中，再加上血液库的清除速度更快，缺乏代谢物具有关键特征，可以增强整体信号与背景比率和目标特异性，以帮助图像分析。 Live Appsw+/ - /PS1（15个月大）中的初步多光子显微镜表明，F-AI-187遍历血脑屏障，以瞬时标记脑实质和血管中的斑块（CAA）（CAA）（CAA）（CAA），并且斑块仍被标记为用于研究时间点。初步的MicroPET/CT成像显示，与其年龄匹配的BL6对应物相比，其在转基因小鼠皮质中的脑部摄取较高（尾巴静脉注射后30分钟），并且其在转基因小鼠的皮质中的保留率与截图与AβPlaques的结合一致。最后，重要的是，该药物对AD是高度特异性的（不显示与其他神经退行性疾病的生物标志物的交叉反应性）；同时还检测PIB-Aβ+ AD病例中的扩散和紧凑斑。在我们的主要销售代理上拥有这些高度挑衅的数据，现在我们建议： 1）对18F-AI-187或第二代铅剂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（靶特异性），WT对等（对照组）和非人类隐私分析（基线SNR）（通过评估时间）（基线）（基线）cretvientive curtivation curtivation curtivation curtivation curtvientive curtivation curtvientive（靶标特异性）中，在年龄匹配的APPSW +/-转基因小鼠（目标特异性）中作为非侵入性Aβ靶向问题的转化潜力（ MicroPET/MR或PET/MR成像，进行动脉代谢物分析和剂量测定研究，以识别高度特定的成像剂，以将转化铅转化为非GMP毒化学研究，以进行EIND归档； 2）进行重点的SAR研究，以开发第二代新型的杂环分子，能够在AD临床表达之前在AD的早期阶段检测Aβ斑块。 3）通过多种结合和胜任的位移评估对第二代Aβ靶向剂进行完整的生化表征，以评估Aβ，评估BBB渗透率和通过生物分布研究和2个photon成像，磷酸化，磷酸化，磷酸化，磷酸化，磷酸化，磷酸化，评估的靶位位点的评估和能力 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，Prion，TDP43和α-同步蛋白）相比，AD脑匀浆和人类AD脑组织切片的AD结合研究包括Aβ的特异性。经过进一步的生化验证，这些新颖的分子成像剂可以在AD的前驱阶段对Aβ进行无创宠物询问，更好地指导AD患者与其他神经退行性疾病的AD患者的分层，并有助于分析新的分子靶向疾病疾病疾病疾病疾病疾病，从而分析AD的整体辅助管理。