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.

项目摘要/摘要 阿尔茨海默氏病（AD）是目前影响数百万患者的主要神经退行性疾病 在美国。由于预计全世界的广告患者人数将显着升级 接下来的十年，建立有效的疗法以减轻毁灭性的广告认知能力是至关重要的 衰落的症状是由于AD大脑病理生理变化而导致的。许多人中的大力研究工作 实验室专注于发现和开发疗法以阻止AD病理生理变化。 胰岛素失调被认为有助于AD的病理生理，脑胰岛素抵抗是 被认为不仅影响关键脑胰岛素受体信号级联反应，还影响胰岛素生长因子1 （IGF1）分别或其他病理变化的级别可能有助于认知 降低广告症状。因此，一种减轻认知症状的治疗方法是 鼻内胰岛素给药，最近在一些早期临床试验中进行了评估。这 初步试验表明，在某些患者AD组中，认知增强和/或稳定性是 通过既定的临床认知评分评估来衡量。我们假设该职位 鼻内胰岛素剂量会导致嗅觉促进大脑和/或肺化促进中枢神经系统胰岛素 吸收机制导致大脑和CSF胰岛素水平差异升高。我们将测试此鼻内 胰岛素假设，因为文献没有有关颞胰岛素浓度变化的信息 在灵长类动物大脑中，鼻内胰岛素剂量和胰岛素CSF增强机制的函数仍然不适 定义。我们的长期目标是为诊所提供一种可行的定量PET成像方法来优化 用于AD和相关患者的鼻内剂量胰岛素治疗。该R21应用程序的目标是建立 概念验证（POC）PET成像平台，将严格评估高特异性活动（HSA） 使用鼻内与静脉内给药路线 在非人类灵长类动物（NHP，恒河猴）中，导致代谢物校正的中枢神经系统和选择外围 组织18F-胰岛素活性分布的测量与与同源示踪剂血液和CSF相关的时间 时间概况。 PET成像评估将使鼻内胰岛素剂量优化 方案，对胰岛素示踪剂如何进入大脑和周围组织有了更详细的了解， 并将建立一个基于宠物成像的18F胰岛素平台，适合翻译，从而实现 AD患者的未来临床PET成像评估。调查目标将通过三个 在二十八个月内进行渐进的特定目标和努力，如下：特定目标1：合成 高特异性活性18F-胰岛素，评估精选示踪剂剂量组成的稳定性，并利用所选的 AIM 2研究的稳定示踪剂量形式；特定目标2：评估目标1确定的HSA 18F-胰岛素 恒河猴中使用测试范式识别最佳鼻内递送 方法，示踪剂CNS和通过定量PET选择外周组织穿透和分布曲线 与相关相比 18F-胰岛素静脉注射措施；和特定目标3：确认目标2 PET成像范式 量化18F-胰岛素CNS并选择随着时间的时间与示踪剂相关的外围组织活性分布 年龄相似的男性和雌性猴子队列的血液和脑脊髓液的特征，从而 定义适用于临床的最佳定量鼻内鼻内传递的18F-胰岛素PET成像方法 成像翻译。