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

摘要/概要 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，从分子水平探讨其作用机制。由于中枢神经系统功能低下 由于第一代α2δ-1 PET示踪剂的渗透性（见初步数据）， PET成像。该提案的重点是开发下一代α2δ-1 PET示踪剂， 预期显示高CNS摄取并且更适合于神经成像。为了达到高中枢神经系统 两类示踪剂，即反式-4-[18F]氟加巴喷丁前药（Aim 1A）和新的 吡唑并哒嗪α2δ-1放射性示踪剂（Aim 1B）。将首先筛选拟议的PET示踪剂 在健康的老鼠身上具有良好CNS渗透性和药代动力学特性的有前途的候选物将是 在健康大鼠和健康非人灵长类动物（NHP）中充分表征（目的2）。我们亦会探讨 新设计的示踪剂在疼痛动物模型和药物成瘾动物模型中的应用， 脊神经结扎（SNL）大鼠和乙醇依赖小鼠（目的3）。我们假设这些 示踪剂将显示出中度到高度的CNS渗透性，并能够检测PET信号变化， 与神经性疼痛和药物成瘾进展相关。该项目将提供必要的 为将来的临床研究提供数据。

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.