Development of a PET Tracer Selective for Cerebral Amyloid Angiopathy

开发选择性脑淀粉样血管病 PET 示踪剂

基本信息

批准号：
9079556
负责人：
Milos D Ikonomovic
金额：
$ 63.28万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9079556
关键词：
Adverse effects Affinity Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloidosis Autoradiography Binding Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrovascular system Cerebrum Chemistry Clinical Trials Congo Red Deposition Detection Development Diagnosis Disease Dyes Fluorescence Future Goals Human Image Immunotherapy In Vitro Infarction Inherited Injection of therapeutic agent Kinetics Label Lead Lesion Life Methods Microscopy Monitor Mus Pathology Patients Penetrance Pharmacology Pilot Projects Pittsburgh Compound-B Positron-Emission Tomography Radiolabeled Recording of previous events Research Risk Senile Plaques Signal Transduction Staging Subjects Selections Techniques Testing Tracer Transgenic Mice Transgenic Organisms Universities amyloid imaging amyloid pathology analog beta amyloid pathology clinical Diagnosis design experience in vivo lipophilicity mouse model multi-photon nanomolar neuropathology novel pre-clinical public health relevance radioligand radiotracer tool

项目摘要

DESCRIPTION (provided by applicant): Positron emission tomography (PET) imaging of hallmark amyloid pathology can facilitate clinical diagnosis of Alzheimer's disease (AD). Our research group at the University of Pittsburgh pioneered development of amyloid-binding PET radioligands by careful preclinical characterization of the Thioflavin-T analog Pittsburgh Compound-B (PiB). Though PiB and longer-lived F-18-labeled Aβ-selective analogs have transformed the field by allowing in vivo detection and monitoring of fibrillar amyloid-β (Aβ) deposits, this technique cannot distinguish between Aβ deposits in brain parenchymal plaques and in blood vessels with cerebral amyloid angiopathy (CAA), which can co-occur in AD brains. Detecting CAA selectively has important implications for AD treatment management and efficacy, because CAA increases the risk of cerebral microhemorrhages which are a side effect of many experimental and promising AD therapies. The objective of this proposal is to develop a novel method to selectively image Aβ-containing CAA in cerebral blood vessels, for use in future clinical trials. Our preliminary studies identified several promising candidate compounds from a panel of analogues of the amyloid-binding dye Congo red (CR). We intend to modify these compounds, aiming to optimize their selectivity for CAA, and to test the most promising compounds in the transgenic APP/PS mouse model which recapitulates AD-defining amyloid plaque pathology as well as CAA. Guided by the lead compounds from our pilot studies, we will synthesize a wide range of novel CR analogues with moderate lipophilicity, and determine their binding affinities to fibrillar Aβ using in vitro binding assays (Aim 1). We are experienced with he chemistry and pharmacology of CR dyes, and have a long, successful history of synthesizing and testing hundreds during the development of PiB and during our preliminary studies of CAA- selective compound candidates. The second major goal of our proposal is to inject these compounds in living APP/PS mice, to assess compound selectivity for CAA vs. parenchymal plaques in ex-vivo histological analyses (Aim 2). In parallel, we will use in-vivo multiphoton microscopy to evaluate further our lead compounds' selectivity for CAA and characterize their brain kinetics in living APP/PS mice (Aim 3). Best candidate CAA-selective compounds will be subsequently radiolabeled and injected in APP/PS mice at nanomolar concentration, as in human PET studies, followed by ex-vivo autoradiography analyses to quantify positive autoradiography signal in CAA vs. parenchymal plaques (Aim 4). Successful completion of these studies will provide novel CAA-selective compounds which can be radiolabeled for use in future PET imaging studies in living people, as a valuable tool to aid in diagnosis and selection of subjects for clinical trials, and to evaluate effects of therapies.

描述（由申请人提供）：标志性淀粉样蛋白病理学的正电子发射断层扫描 (PET) 成像可以在临床上促进阿尔茨海默病 (AD) 的诊断。我们匹兹堡大学的研究小组通过仔细的临床前表征，率先开发了淀粉样蛋白结合 PET 放射性配体。硫磺素-T 类似物匹兹堡化合物-B (PiB)，尽管 PiB 和寿命较长的 F-18 标记的 Aβ 选择性类似物。通过允许体内检测和监测纤维状淀粉样蛋白-β (Aβ) 沉积物，该技术改变了该领域，但该技术无法区分脑实质斑块中的 Aβ 沉积物和患有脑淀粉样血管病 (CAA) 的血管中的 Aβ 沉积物，而脑淀粉样蛋白血管病 (CAA) 可能同时发生选择性检测 CAA 对 AD 治疗管理和疗效具有重要意义，因为 CAA 会增加脑微出血的风险，而脑微出血是许多实验性和有前景的 AD 疗法的副作用。本提案旨在开发一种新方法，选择性地对脑血管中含有 Aβ 的 CAA 进行成像，用于未来的临床试验。我们的初步研究从淀粉样蛋白结合染料刚果红 (CR) 的类似物中确定了几种有前途的候选化合物。我们打算修改这些化合物，旨在优化它们对 CAA 的选择性，并在转基因 APP/PS 小鼠模型中测试最有前途的化合物，该模型概括了 AD 定义的淀粉样斑块病理学以及 CAA。在我们的试点研究中的先导化合物的指导下，我们将合成一系列具有中等亲脂性的新型 CR 类似物，并使用体外结合测定法确定它们与纤维状 Aβ 的结合亲和力（目标 1）。 CR 染料，并且在 PiB 的开发过程中以及在我们对 CAA 选择性化合物候选物的初步研究过程中拥有合成和测试数百种化合物的悠久而成功的历史。我们建议的第二个主要目标是注射这些化合物。在活体 APP/PS 小鼠中，在离体组织学分析中评估化合物对 CAA 与实质斑块的选择性（目标 2）。同时，我们将使用体内多光子显微镜进一步评估我们的先导化合物对 CAA 和实质斑块的选择性。表征活体 APP/PS 小鼠的大脑动力学（目标 3），随后将在 APP/PS 小鼠体内进行放射性标记和注射。纳摩尔，如在人类 PET 研究中，然后进行离体放射自显影分析，以量化 CAA 与实质斑块中的阳性放射自显影信号（目标 4），这些研究的成功完成将提供可进行放射性标记的新型 CAA 选择性化合物。未来对活人进行 PET 成像研究，作为帮助诊断和选择临床试验受试者以及评估治疗效果的宝贵工具。