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

项目总结/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2015年显著增加， 下一个十年，迫切需要建立有效的治疗方法来减轻毁灭性的AD认知障碍。 衰退症状是AD脑中病理生理变化的结果。在许多领域开展了积极的研究工作 实验室专注于发现和开发阻止AD病理生理学变化的疗法。 胰岛素失调被认为有助于AD的病理生理学，由此脑胰岛素抵抗被抑制。 被认为不仅影响关键的脑胰岛素受体信号级联，而且影响胰岛素生长因子1 （IGF 1）水平，共同，单独或辅助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通过 鼻内给药胰岛素，最近在一些早期临床试验中进行了评估。的 初步试验显示，在一些AD患者组中，认知增强和/或稳定性是 通过已建立的临床认知评分评估来衡量。我们假设这篇文章 鼻内胰岛素给药引起嗅觉易化的脑和/或肺-肠易化的CNS胰岛素 摄取机制导致脑和CSF胰岛素水平差异性升高。我们将通过鼻内测试 胰岛素假说，因为文献缺乏关于胰岛素浓度时间变化的信息 在活灵长类动物脑中，作为鼻内胰岛素给药的功能和胰岛素CSF增强机制仍然是病态的 定义了我们的长期目标是为临床提供一种可行的定量PET成像方法， 用于AD和相关患者的鼻内给药胰岛素疗法。此R21应用程序的目标是建立 概念验证（POC）PET成像平台，将严格评估高比活度（HSA） 使用鼻内与静脉内给药途径的氟-18（18F）胰岛素（18F-胰岛素）剂量组合物 在非人灵长类动物（NHP，恒河猴）中，导致代谢物校正的CNS和选择的外周 与同源示踪剂血液和CSF相关的组织18F-胰岛素活性分布测量值与时间 时间剖面PET成像评估将能够优化鼻内胰岛素给药 方案，提供了更详细的了解胰岛素示踪剂如何进入大脑和外周组织， 并将建立基于PET成像的18F-胰岛素平台，该平台将适合于平移，从而使 AD患者的未来临床PET成像评估。调查目标将通过三个方面来实现 在28个月期间逐步实现具体目标和努力，具体目标1： 高比活度18F-胰岛素，评价所选示踪剂剂量组合物稳定性，并利用所选的 目标2研究的稳定示踪剂剂型;具体目标2：评价目标1确定的HSA 18 F-胰岛素 在恒河猴中使用测试-再测试范例以确定最佳鼻内递送的示踪剂剂型 方法，示踪剂中枢神经系统和选择外周组织渗透和分布的定量PET 影像学测定结合18F-胰岛素血液和脑脊液分析，与相关 18F-胰岛素静脉给药测量;和特定目标3：通过以下方式确认目标2 PET成像范例： 定量18F-胰岛素CNS和选择与示踪剂相关的随时间的外周组织活性分布 年龄相似的雄性和雌性猴队列组中血液和脑脊液的特征，从而 定义适合临床应用的最佳定量鼻内递送18F-胰岛素PET成像方法 图像翻译

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.