PET Imaging Agents for the in vivo Detection of TDP-43

用于 TDP-43 体内检测的 PET 成像剂

基本信息

批准号：
9409556
负责人：
Allen Bernard Reitz
金额：
$ 74.54万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9409556
关键词：
4-aminoquinoline ABCB1 gene Affect Alzheimer&apos s Disease Amyloid Amyotrophic Lateral Sclerosis Animal Model Animals Applications Grants Area Back Baltimore Binding Biochemical Biodistribution Biological Assay Blood - brain barrier anatomy Brain C-terminal Caregivers Cell Line Cell Nucleus Cells Cessation of life Characteristics Chemicals Conduct Clinical Trials Cytoplasm Cytoplasmic Granules Cytosol DNA-Binding Proteins Dementia Detection Development Diagnosis Disease Disease Progression Dose Drug Kinetics Early Diagnosis Ensure Evaluation Familial Amyotrophic Lateral Sclerosis Fluorescent Probes Frontotemporal Lobar Degenerations Funding Generations Genetic Transcription Glycine Hand Human Human Resources Image In Vitro Individual Injectable Label Ligand Binding Ligands Link Liver Microsomes Lobar Measures Metabolic Methods Modeling Modernization Monitor Mus Mutation Neuraxis Neurologic Neurons Nucleic Acids Oligonucleotides Outcome P-Glycoprotein Pathologic Pathology Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Positron Positron-Emission Tomography Preparation Property Proteins Publishing Quantitative Autoradiography RNA Radiolabeled Radiopharmaceuticals Rattus Reagent Regulator Genes Reporting Research Personnel Rodent Route Single-Stranded DNA Specificity Specimen Spinal Cord Spliced Genes Structure Structure-Activity Relationship Synthesis Chemistry Therapeutic Time Tissues Tracer Transgenic Mice Translational Research Treatment Efficacy Validation accurate diagnosis amyloid imaging base biophysical properties clinical toxicology culture plates design disease diagnosis dosimetry experience imaging agent immortalized cell in vitro testing in vivo in vivo imaging individual patient innovation male nervous system disorder nonhuman primate novel novel therapeutics nucleic acid binding protein pharmacophore pre-clinical protein TDP-43 radioligand radiotracer receptor response small molecule tau Proteins uptake

项目摘要

Amyotrophic lateral sclerosis (ALS) and frontotemperal lobar degeneration (FTLD) are debilitating neurological disorders that cause extreme suffering to patients and caregivers alike. Affected neurons in the spinal cord and brain of patients with ALS and FTLD are characterized for many individuals by having too much ubiquinylated and misfolded inclusions of cytosolic trans-activating response (TAR) DNA binding protein TDP-43. It is estimated that half of FTLD patients have associated TDP-43 pathology, making TDP-43-associated FTLD the single largest subtype. TDP-43 is also a key component of the ubiquitinated inclusions found in the cytosol of most patients with ALS, especially sporadic ALS (sALS, 85-90% of patients). In addition, numerous mutations in TDP-43, particularly in the glycine-rich C-terminal domain, are linked to familial ALS (fALS). The translational research effort described in this grant application seeks to identify selective radiotracers that image TDP-43 in real time in the brain or spinal cord of relevant patient via positron emission tomography (PET). Unlike for amyloid (e.g. florbetapir) and tau, no TDP-43 radiotracers have been reported to date. PET ligands for ALS and FTLD are expected to provide early and more accurate diagnosis of disease, help to monitor the progression of disease over time, and evaluate whether various therapeutic treatments are having a positive effect in individual patients. We have discovered new small-molecule probes that bind to TDP-43 using an alpha-screen assay that we developed, and here propose to further refine and validate these as radiotracers, including in animal models such as transgenic mice and normal non-human primates. Aim 1 is to obtain more potent TDP-43 binders as candidates for 18F or 11C hot ligand synthesis, by conducting iterative SAR development preparing ~200-250 new chemical entities (NCEs) to obtain small molecule candidates that bind to TDP-43 with PET-suitable biophysical properties, using modern methods of medicinal chemistry, structure-based design, pharmacophore development and synthetic chemistry. Biochemical characterization will use our alpha-screen assay and evaluation of binding to pathologically-relevant misfolded TDP-43. ADME characterization will ensure that the biophysical properties of the top leads selected are amenable for PET. In Aim 2, we will prepare radiolabeled TDP-43 binding ligands suitable for in vivo imaging based on top Aim 1 leads, an area of expertise for which Marty Pomper, Johns Hopkins, key personnel on the application, has considerable experience. Finally, in Aim 3, we seek to validate one or more TDP-43 PET ligands using ex vivo and in vivo methods including in vivo characterization in TDP-43 transgenic mice, TDP-43-NLS mice and normal non-human primates, with a desired outcome of >80% specific TDP-43 blockade. It is expected that at the end of this two year funding period we will have in hand at least one compound en route to an IND application. An example of commercial use would be to confirm a TDP-43-based diagnosis for dementia caused by FTLD, when compared to the amyloid-associated Alzheimer's disease.

肌萎缩性侧索硬化症（ALS）和额气叶片变性（FTLD）正在使神经系统衰弱给患者和看护人带来极端痛苦的疾病。脊髓中的神经元和 ALS和FTLD患者的大脑对许多个体的泛素化表征并折叠的胞质反式激活反应（TAR）DNA结合蛋白TDP-43的夹杂物。这是估计一半的FTLD患者患有TDP-43病理学，使TDP-43相关的FTLD 最大的亚型。 TDP-43也是在细胞质中发现的泛素化夹杂物的关键组成部分大多数ALS患者，尤其是零星ALS（SALS，85-90％的患者）。另外，许多突变在TDP-43中，特别是在富含甘氨酸的C末端结构域中，与家族ALS（fals）有关。这本赠款申请中描述的翻译研究工作旨在确定选择性的放射性示踪剂图像TDP-43实时在大脑或相关患者的脊髓中通过正电子发射断层扫描（宠物）。与淀粉样蛋白（例如Florbetapir）和Tau不同，迄今为止，尚无TDP-43放射性示例。宠物 ALS和FTLD的配体有望提供早期，更准确的疾病诊断，有助于随着时间的流逝，监测疾病的进展，并评估是否有各种治疗治疗对个别患者的积极作用。我们发现了与TDP-43结合的新的小分子问题使用我们开发的α-屏幕测定放射性示例，包括在动物模型中，例如转基因小鼠和正常的非人类隐私。目标1是通过进行迭代，获得更多潜在的TDP-43粘合剂作为18F或11C热配体合成的候选物制备〜200-250新化学实体（NCE）的SAR开发以获得小分子候选者使用现代药物化学方法与宠物合适的生物物理特性与TDP-43结合，基于结构的设计，药效团发育和合成化学。生化特征将使用我们的α-屏幕测定法以及对与病理相关的错误折叠的TDP-43的结合评估。 adme 表征将确保所选顶部铅的生物物理特性适合PET。在 AIM 2，我们将准备放射标记的TDP-43结合配体，适用于基于顶部目标1的体内成像1 Leads是Marty Pomper，Johns Hopkins的专业知识领域丰富的经验。最后，在AIM 3中，我们寻求使用离体验证一个或多个TDP-43 PET配体和体内方法，包括TDP-43转基因小鼠，TDP-43-NLS小鼠和正常的非人类隐私，预期的结果> 80％特异性TDP-43封锁。预计在在这两年的资金期结束时，我们将至少有一种途径在通往IND的途中应用。商业用途的一个例子是确认基于TDP-43的痴呆诊断由FTLD引起的，与淀粉样蛋白相关的阿尔茨海默氏病相比。