Development of next generation of α2δ-1 PET tracers for neuroimaging

开发用于神经影像的下一代α2β-1 PET示踪剂

• 批准号: 10507390
• 负责人: Yu-Peng ZHOU
• 金额: $ 9.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507390
• 关键词: Address; Affinity; Animal Model; Autoradiography; Binding; Biochemical Process; Biodistribution; Blood; Brain; Calcium Channel; Carbon; Categories; Clinical Research; Clinical Trials; Data; Detection; Development; Disease; Drug Addiction; Drug Kinetics; Drug Modelings; Ethanol dependence; Evaluation; FDA approved; Filament; Fluorine; Future; Generations; Health; Image; Imaging Device; Immunohistochemistry; In Vitro; Label; Lesion; Ligation; Measures; Metabolic; Methods; Molecular; Mus; Nerve; Neuropathy; Opioid; Pain; Permeability; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Prodrugs; Property; Proteins; Rattus; Rodent; Role; Signal Transduction; Spinal nerve structure; System; Testing; Therapeutic; Tracer; X-Ray Computed Tomography; addiction; analog; base; behavior test; design; dosimetry; experimental study; gabapentin; glucose metabolism; in vivo; microPET/CT; molecular imaging; neurochemistry; neuroimaging; neurotransmission; next generation; nonhuman primate; novel; overexpression; pain model; painful neuropathy; radiotracer; receptor; small molecule; tool; uptake; voltage

Abstract/summary PET imaging can be potentially used to quantify biochemical processes underlying pain and drug addiction mechanisms at molecular level by detecting the expression level of α2δ-1 receptor. Due to the low CNS permeability of the first generation of α2δ-1 PET tracers (see preliminary data), the lesion cannot be detected by PET imaging. This proposal is focused on the development of the next generation of α2δ-1 PET tracers, which are expected to show high CNS uptake and be more suitable for neuroimaging. In order to achieve the high CNS permeability, two categories of tracers, namely trans-4-[18F]fluorogabapentin prodrug (Aim 1A) and novel pyrazolopyridazine α2δ-1 radiotracer (Aim 1B), are proposed. The proposed PET tracers will be first screened in heathy mice. The promising candidates with good CNS permeability and pharmacokinetic properties will be fully characterized in health rats, and healthy non-human primates (NHPs) (Aim 2). We will also explore the applications of newly designed tracers in animal models of pain and animal models of drug addiction such as spinal nerve ligation (SNL) rats and ethanol dependence mice, respectively (Aim 3). We hypothesize these tracers will show moderate to high CNS permeability and enable the detection of PET signal changes that correlate with the neuropathic pain and drug addiction progression. The proposed project will provide necessary data for a future clinical study.

摘要/总结 PET 成像可用于量化疼痛和药物成瘾的生化过程 通过检测α2δ-1受体的表达水平在分子水平上探讨机制。由于中枢神经系统低 第一代α2δ-1 PET示踪剂的渗透性（见初步数据），无法检测到病变 PET 成像。该提案的重点是开发下一代 α2δ-1 PET 示踪剂，该示踪剂 预计表现出高中枢神经系统摄取并且更适合神经影像学。为了达到高CNS 渗透性，两类示踪剂，即反式 4-[18F]氟加巴喷丁前药 (Aim 1A) 和新型示踪剂 提出了吡唑并哒嗪 α2δ-1 放射性示踪剂（目标 1B）。拟议的 PET 示踪剂将首先进行筛选 在健康的小鼠中。具有良好中枢神经系统渗透性和药代动力学特性的有前途的候选药物将是 在健康大鼠和健康非人类灵长类动物 (NHP) 中得到充分表征（目标 2）。我们还将探索 新设计的示踪剂在疼痛动物模型和毒瘾动物模型中的应用，例如 分别是脊髓神经结扎 (SNL) 大鼠和乙醇依赖小鼠（目标 3）。我们假设这些 示踪剂将表现出中等到高的 CNS 渗透性，并能够检测 PET 信号变化，这些变化 与神经性疼痛和药物成瘾进展相关。拟议的项目将提供必要的 为未来的临床研究提供数据。