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

用于 TDP-43 体内检测的 PET 成像剂

• 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
• 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' 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

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）是使人衰弱的神经系统疾病， 对病人和护理人员都造成极大痛苦的疾病。脊髓中受影响的神经元， ALS和FTLD患者的脑的特征在于许多个体具有太多的泛醌化 和胞质反式激活反应（TAR）DNA结合蛋白TDP-43的错误折叠内含物。是 估计有一半的FTLD患者具有与TDP-43相关的病理学，使得TDP-43相关的FTLD成为可能。 单一最大亚型。TDP-43也是在大肠杆菌胞质溶胶中发现的泛素化包涵体的关键组分。 大多数ALS患者，尤其是散发性ALS（sALS，85-90%的患者）。此外，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，与家族性ALS（fALS）有关。的 在该资助申请中描述的转化研究努力寻求鉴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脑或脊髓中的TDP-43进行真实的实时成像 （PET）。与淀粉样蛋白（例如florbetapir）和tau不同，迄今为止尚未报道TDP-43放射性示踪剂。宠物 ALS和FTLD的配体有望提供早期和更准确的疾病诊断， 监测疾病随时间的进展，并评估各种治疗方法是否具有 对个体患者有积极影响。我们已经发现了新的小分子探针结合TDP-43 使用我们开发的α筛选试验，并在此建议进一步完善和验证这些， 放射性示踪剂，包括在动物模型如转基因小鼠和正常的非人灵长类动物中。目标1是 获得更有效的TDP-43结合剂作为18F或11 C热配体合成的候选物，通过进行迭代 SAR开发准备约200-250个新的化学实体（NCE），以获得小分子候选物， 结合TDP-43与PET合适的生物物理特性，使用现代药物化学方法， 基于结构设计、药效团开发和合成化学。生物化学表征 将使用我们的α-筛选测定和与病理相关的错误折叠TDP-43的结合的评价。ADME 表征将确保所选顶部电极导线的生物物理特性适合PET。在 目的2：在目的1的基础上，制备适合于体内显像的TDP-43结合配体 线索，这是一个专业领域，马蒂庞珀，约翰霍普金斯，对应用程序的关键人员， 相当丰富的经验。最后，在目标3中，我们寻求使用离体方法验证一种或多种TDP-43 PET配体。 和体内方法，包括在TDP-43转基因小鼠、TDP-43-NLS小鼠和 正常非人灵长类动物，具有>80%特异性TDP-43阻断的期望结果。预计在 在这两年的资助期结束时，我们将至少有一种化合物正在向IND申请 应用程序.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病相比，