Nonhuman Primate CNS Assessments of 18F-Insulin After IntranasalAdministration

项目摘要/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。由于全球阿尔茨海默病患者的数量预计将在 未来十年，迫切需要建立有效的治疗方法来缓解毁灭性的AD认知 阿尔茨海默病(AD)脑内病理生理变化所致的衰弱症状。在许多方面做出了积极的研究努力 实验室专注于发现和开发阻止AD病理生理变化的治疗方法。 胰岛素失调被认为是阿尔茨海默病的病理生理机制之一，大脑胰岛素抵抗是 被认为不仅影响关键的大脑胰岛素受体信号级联反应，而且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 减轻阿尔茨海默病症状。因此，缓解认知衰退症状的一种治疗方法是通过 鼻腔注射胰岛素，最近在几个早期临床试验中进行了评估。这个 初步试验表明，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。我们假设这个帖子 鼻腔给药引起嗅觉易化脑和/或肺-肠易化中枢胰岛素 导致脑和脑脊液胰岛素水平不同升高的摄取机制。我们会在鼻腔内测试这个 胰岛素假说，因为文献中缺乏有关胰岛素浓度时间变化的信息 活体灵长类动物脑内胰岛素鼻腔给药和胰岛素-脑脊液增强机制仍处于病态状态 已定义。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，以优化 一种针对AD及相关患者的鼻腔给药胰岛素疗法。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) 氟-18(18F)胰岛素(18F-胰岛素)鼻腔给药与静脉给药的剂量组成 在非人灵长类动物(NHP、恒河猴)中，导致代谢物纠正CNS和选择外周 组织~(18)F-胰岛素活性分布与同种示踪剂血和脑脊液的关系 时间档案。PET成像评估将使优化鼻腔内胰岛素给药成为可能 方案，提供了更详细的了解胰岛素示踪剂是如何进入大脑和周围组织的， 并将建立适合翻译的基于PET成像的18F-胰岛素平台，从而实现 阿尔茨海默病患者未来临床PET影像评价。调查目标将在三个方面完成 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，评价所选示踪剂量组合物的稳定性，并利用所选 Aim 2研究的稳定示踪剂量形式；特定目标2：评估Aim 1确定的HSA 18F-胰岛素 用重测范式确定最佳鼻腔给药在恒河猴体内的示踪剂量形式 方法：用定量正电子发射计算机断层扫描技术示踪中枢神经系统，选择周围组织的穿透和分布特征 ~(18)F-胰岛素血和脑脊液成像测定与相关的比较 18F-胰岛素静脉给药措施；和特定目标3：通过以下方式确认目标2 PET成像范式 定量18F-胰岛素中枢神经系统并选择与示踪剂相关的外周组织活动随时间的分布 年龄相近的雄性和雌性猕猴队列组的血液和脑脊液的特征，从而 一种适合临床的鼻腔定量18F-胰岛素PET显像方法的确定 成像翻译。

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.