Nonhuman Primate CNS Assessments of 18F-Insulin After Intranasal Administration

鼻内给药后 18F-胰岛素的非人灵长类 CNS 评估

• 批准号: 9226873
• 负责人: JOHN M GERDES
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226873
• 关键词: Active Biological Transport; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Disease Models; Animal Model; Apoptosis; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Breathing; Cells; Cerebrospinal Fluid; Cerebrum; Clinic; Clinical; Clinical Trials; Cognitive; Cognitive Therapy; Collection; Coupled; Deposition; Distributional Activity; Dose; Enteral; Evaluation; Female; Formulation; Functional disorder; Future; Genotype; Glucose; Goals; Growth Factor; Growth Factor Receptors; Human; Image; Impaired cognition; Insulin; Insulin Receptor; Insulin Resistance; Intestinal Absorption; Intranasal Administration; Intravenous; Investigation; Label; Laboratories; Literature; Lung; Macaca mulatta; Measures; Methods; Monkeys; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Penetration; Peripheral; Phase; Positron; Positron-Emission Tomography; Primates; Protocols documentation; Radiolabeled; Receptor Signaling; Regimen; Reporting; Reproducibility; Research; Route; Structure of mucous membrane of nose; Symptoms; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tracer; Translations; United States; absorption; apolipoprotein E-4; base; capillary; clinical imaging; cognitive enhancement; cognitive function; cohort; effective therapy; hyperphosphorylated tau; imaging approach; imaging modality; imaging platform; imaging study; intravenous administration; male; nonhuman primate; novel; theories; therapy development; uptake

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the leading neurodegenerative disorder presently affecting several million patients in the United States. Since the number of AD patients worldwide is anticipated to significantly escalate over the next decade, there is a critical need to establish effective therapies to alleviate the devastating AD cognitive decline symptoms that are result of pathophysiological changes in AD brain. Vigorous research efforts in many laboratories are focused upon discovering and developing therapies to halt AD pathophysiological changes. Insulin dysregulation is thought to contribute to the pathophysiology of AD, whereby brain insulin resistance is considered to affect not only critical brain insulin receptor signaling cascades but also insulin growth factor 1 (IGF1) levels that together, separately or adjunct to other pathological changes may contribute to cognitive decline AD symptoms. Hence, one therapeutic approach to alleviate cognitive decline symptoms is by the intranasal administration of insulin, which has been recently evaluated in a few early phase clinical trials. The preliminary trials have revealed that in some patient AD groups, cognitive enhancement and/or stability are realized as measured by established clinical cognitive scoring assessments. We hypothesize that post intranasal insulin dosing causes olfactory facilitated brain and/or pulmonary-enteric facilitated CNS insulin uptake mechanisms resulting in differentially elevated brain and CSF insulin levels. We will test this intranasal insulin hypothesis since the literature is devoid of information regarding temporal insulin concentration changes in live primate brain as a function of intranasal insulin dosing and insulin CSF enhancing mechanisms remain ill defined. Our long-term objective is to provide the clinic a viable quantitative PET imaging approach to optimize an intranasal dosed insulin therapy for AD and related patients. The goal of this R21 application is to establish a proof-of-concept (POC) PET imaging platform that will rigorously assess high specific activity (HSA) fluourine-18 (18F) insulin (18F-insulin) dose compositions using intranasal vs. intravenous administration routes in nonhuman primates (NHPs, rhesus monkeys), resulting in metabolite corrected CNS and select peripheral tissue 18F-insulin activity distribution measures vs. time as correlated to cognate tracer blood and CSF temporal profiles. The PET imaging assessments will enable optimization of the intranasal insulin dosing regimen, afford a more detailed understanding of how the insulin tracer gets into brain and peripheral tissues, and will establish a PET imaging based 18F-insulin platform that will be suitable for translation, thereby enabling future clinical PET imaging appraisals of AD patients. The investigation goal will be accomplished with three progressive specific aims and efforts over a twenty-eight month period, as follows: Specific Aim 1: Synthesize high specific activity 18F-insulin, evaluate stabilities of select tracer dose compositions, and utilize selected stable tracer dose forms for the Aim 2 studies; Specific Aim 2: Evaluate the Aim 1 identified HSA 18F-insulin tracer dose forms in rhesus monkeys using a test-retest paradigm to identify optimal intranasal delivery methods, tracer CNS and select peripheral tissue penetration and distribution profiles by quantitative PET imaging determinations coupled to18F-insulin blood and cerebral spinal fluid profiling, as compared to related 18F-insulin intravenous dosed measures; and Specific Aim 3: Confirm the Aim 2 PET imaging paradigm by quantifying 18F-insulin CNS and select peripheral tissue activity distributions over time correlated to tracer profiles in blood and cerebral spinal fluid in age similar male and female monkey cohort groups, thereby defining an optimal quantitative intranasal delivered 18F-insulin PET imaging approach suitable for clinical imaging translation.

项目概要/摘要 阿尔茨海默病 (AD) 是目前影响数百万患者的主要神经退行性疾病 在美国。由于预计全球 AD 患者数量将在 下一个十年，迫切需要建立有效的疗法来减轻破坏性的AD认知 减少 AD 大脑病理生理变化导致的症状。多方面的积极研究工作 实验室致力于发现和开发阻止 AD 病理生理变化的疗法。 胰岛素失调被认为是导致 AD 病理生理学的原因之一，即大脑胰岛素抵抗 人们认为不仅影响关键的大脑胰岛素受体信号级联，还影响胰岛素生长因子 1 (IGF1) 水平共同、单独或伴随其他病理变化可能有助于认知 减少 AD 症状。因此，缓解认知衰退症状的一种治疗方法是 鼻内注射胰岛素，最近已在一些早期临床试验中进行了评估。这 初步试验表明，在一些 AD 患者组中，认知能力增强和/或稳定性 通过已建立的临床认知评分评估来衡量实现的。我们假设该帖子 鼻内胰岛素给药会导致嗅觉促进脑和/或肺肠促进中枢神经系统胰岛素 摄取机制导致大脑和脑脊液胰岛素水平差异升高。我们将测试这种鼻内 胰岛素假说，因为文献缺乏有关胰岛素浓度暂时变化的信息 在活体灵长类动物大脑中，鼻内胰岛素剂量和胰岛素脑脊液增强机制的作用仍然存在问题 定义的。我们的长期目标是为诊所提供可行的定量 PET 成像方法来优化 针对 AD 及相关患者的鼻内给药胰岛素治疗。此 R21 应用程序的目标是建立 概念验证 (POC) PET 成像平台，将严格评估高比活性 (HSA) 使用鼻内与静脉内施用途径的氟-18(18F)胰岛素(18F-胰岛素)剂量组合物 在非人类灵长类动物（NHP、恒河猴）中，导致代谢物校正中枢神经系统并选择外周 组织 18F-胰岛素活性分布测量与时间的关系，与同源示踪血液和脑脊液相关 时间概况。 PET 成像评估将能够优化鼻内胰岛素剂量 方案，更详细地了解胰岛素示踪剂如何进入大脑和周围组织， 并将建立一个基于 PET 成像的 18F-胰岛素平台，该平台将适合翻译，从而使 AD 患者未来的临床 PET 成像评估。调查目标将通过三 在 28 个月期间逐步实现的具体目标和努力如下： 具体目标 1：综合 高比活性 18F-胰岛素，评估选定示踪剂剂量组合物的稳定性，并利用选定的 用于 Aim 2 研究的稳定示踪剂剂型；具体目标 2：评估目标 1 确定的 HSA 18F-胰岛素 使用重测范例在恒河猴中使用示踪剂剂型来确定最佳鼻内递送 方法，示踪中枢神经系统并通过定量 PET 选择外周组织渗透和分布曲线 与相关的 18 F-胰岛素血液和脑脊液分析相结合的成像测定 18F-胰岛素静脉给药措施；和具体目标 3：确认 Aim 2 PET 成像范例 量化 18F-胰岛素 CNS 并选择与示踪剂相关的随时间变化的外周组织活动分布 年龄相似的雄性和雌性猴子队列组中血液和脑脊液的分布情况，从而 定义适合临床的最佳定量鼻内输送 18F-胰岛素 PET 成像方法 影像翻译。