Sigma-1 Receptors: A Novel Clinical Target in Fragile X Syndrome

摘要： 脆性X综合征是一种衰弱的神经遗传性疾病，可导致多种功能障碍 认知、记忆和学习。社会情绪、认知和行为领域的适应不良功能 极大地阻碍教育和社会发展，导致持续到成年的功能障碍。目前， 建议使用抗精神病药物、抗抑郁药物和情绪稳定剂等药物。 与行为干预相结合，重点是对症治疗。除了拥有 严重的副作用，长期使用这些药物会进一步阻碍认知能力。因此，有针对性的 药物治疗对于缓解这些挑战和促进最佳发展至关重要。近期 有证据表明Sigma-1受体配体(S1R)是一类潜在的新型神经保护剂。 Sigma-1受体(S1R)广泛分布于大脑各处，在那里它们与离子通道和 神经递质在认知、学习和记忆功能中起着关键作用。在这项提案中，我们 将使用我们的S1R选择性显像剂18F-FTC-146和正电子发射断层扫描(PET)开始 了解S1Rs在男性FXS中的功能作用。我们将翻译和探索临床- 18F-FTC-146PET-MR成像研究男性FXS患者的S1R密度因此，我们假设 使用我们的高选择性S1R放射性配基(18F-FTC-146)进行PET-MR成像将是一种有用的研究策略 S1Rs在治疗FXS中的潜在作用。我们的成像方法，利用PET和MR成像，有望 帮助临床医生更好地开发和选择靶向治疗并监测治疗反应。此外，它还 将使研究FXS和CAN的病理生理学和治疗的多学科的研究人员受益 显著提高智障家庭和个人的生活质量。

SUMMARY: Fragile X syndrome is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Maladaptive functioning in socio-emotional, cognitive and behavioral domains greatly hinder educational and social development resulting in dysfunction that persists into adulthood. Currently, pharmacological agents such as antipsychotics, antidepressants, and mood stabilizers are recommended in conjunction with behavioral intervention and are focused on symptomatic treatment. In addition to having significant side effects, long term use of these agents can further impede cognitive ability. Therefore, targeted pharmacological treatment is crucial to mitigate these challenges and facilitate optimal development. Recent evidence has brought forth sigma-1 receptor ligands (S1R) as a potential new class of neuroprotective agents. Sigma-1 receptors (S1R) are widely distributed throughout the brain where they interact with ion channels and neurotransmitters and play a critical role in the function of cognition, learning and memory. In this proposal, we will employ our S1R-selective imaging agent, 18F-FTC-146, with positron emission tomography (PET) to begin understanding the functional role of S1Rs in males with FXS. We will translate and explore the utility of clinical- grade 18F-FTC-146 PET-MR imaging to investigate S1R density in males with FXS. Thus, we hypothesize that PET-MR imaging with our highly selective S1R radioligand (18F-FTC-146) will be a useful strategy for studying the potential role of S1Rs for treating FXS. Our imaging approach, utilizing PET and MR imaging, promises to aid clinicians to better develop and select targeted treatments and monitoring treatment response. In addition, it will benefit researchers in multiple disciplines studying the pathophysiology and treatment of FXS and can significantly improve quality of life for families and individuals with intellectual disabilities.