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

摘要/摘要 PET成像可能被用来量化疼痛和药物成瘾的生化过程 检测α-2、δ-1受体表达水平在分子水平上的作用机制。由于CNS较低 第一代α2δ-1PET示踪剂的渗透性(见初步数据)，病变无法通过 宠物成像。这项建议的重点是开发下一代α2δ-1PET示踪剂，该示踪剂 有望表现出较高的中枢神经系统摄取，更适合于神经成像。为了达到较高的CNS 渗透性，两类示踪剂，即反式-4-[18F]氟卡巴喷丁前药(目标1A)和新型 提出了α-2-δ-1放射性示踪剂(Aim 1B)。建议的PET示踪剂将首先进行筛选 在健康的小鼠身上。具有良好的中枢神经系统渗透性和药代动力学特性的候选药物将是 在健康的大鼠和健康的非人类灵长类(NHP)中充分表现出特征(目标2)。我们还将探索 新设计的示踪剂在疼痛动物模型和药物成瘾动物模型中的应用 脊髓神经结扎(SNL)大鼠和酒精依赖小鼠(目标3)。我们假设这些 示踪剂将显示中到高的中枢神经系统通透性，并能够检测到PET信号的变化 与神经病理性疼痛和药物成瘾进展相关。拟议的项目将提供必要的 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.