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.

肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 会导致神经衰弱给患者和护理人员带来极大痛苦的疾病，受影响的脊髓和神经元。许多 ALS 和 FTLD 患者的大脑特点是具有过多的泛素化以及胞质反式激活反应 (TAR) DNA 结合蛋白 TDP-43 的错误折叠内含物。据估计，一半的 FTLD 患者具有相关的 TDP-43 病理学，这使得 TDP-43 相关的 FTLD 成为 TDP-43 也是胞浆中发现的泛素化内含物的关键组成部分。大多数ALS患者，尤其是散发性ALS（sALS，85-90%的患者）此外还有大量突变。 TDP-43 中，特别是富含甘氨酸的 C 端结构域，与家族性 ALS (fALS) 相关。本拨款申请中描述的转化研究工作旨在确定选择性放射性示踪剂通过正电子发射断层扫描对相关患者的大脑或脊髓中的 TDP-43 进行实时成像 (PET)。与淀粉样蛋白（例如弗洛贝吡）和 tau 蛋白不同，迄今为止尚未报道 TDP-43 放射性示踪剂。 ALS 和 FTLD 的配体有望提供早期、更准确的疾病诊断，有助于监测疾病随时间的进展，并评估各种治疗方法是否有效我们发现了与 TDP-43 结合的新小分子探针。使用我们开发的 alpha 筛选测定法，并在此建议进一步完善和验证这些测定法放射性示踪剂，包括转基因小鼠和正常非人类灵长类动物模型中的目标1是。通过迭代获得更有效的 TDP-43 结合物作为 18F 或 11C 热配体合成的候选物 SAR 开发准备约 200-250 个新化学实体 (NCE) 以获得小分子候选物使用现代药物化学方法，与具有 PET 适合的生物物理特性的 TDP-43 结合，基于结构的设计、药效团开发和合成化学。将使用我们的 α 筛选测定和评估与病理相关的错误折叠 ADME 的结合。表征将确保所选顶级引线的生物物理特性适合 PET。目标2，我们将在首要目标1的基础上制备适合体内成像的放射性标记的TDP-43结合配体领导者，约翰·霍普金斯大学的马蒂·庞珀（Marty Pomper）是该应用程序的关键人员，该领域的专业知识最后，在目标 3 中，我们寻求使用离体验证一种或多种 TDP-43 PET 配体。和体内方法，包括 TDP-43 转基因小鼠、TDP-43-NLS 小鼠和正常非人类灵长类动物，预计具有 >80% 的特异性 TDP-43 阻断效果。在这两年的资助期结束时，我们将拥有至少一种正在进入 IND 的化合物商业用途的一个例子是确认基于 TDP-43 的痴呆症诊断。与淀粉样蛋白相关的阿尔茨海默氏病相比，由 FTLD 引起。