Development of 18F-Labeled Agonist PET Probes for Quantifying 5-HT1A Receptors

描述(申请人提供)：这项建议旨在开发一种18F标记的激动剂PET探针，用于在体内定量狒狒体内G蛋白偶联的高亲和力5-HT1A(5-HT1A)受体。我们开发18F标记的5-HT1a受体激动剂放射性示踪剂有两个主要动机。首先，我们之前已经证明，5-HT1a受体在重度抑郁症中异常，结合增加预示着对抗抑郁药物的反应。将这项技术用于临床的主要障碍之一是能够生产C-11标记放射性示踪剂的中心数量有限。F-18追踪器可以运往距离生产地点4小时半径内的多个医疗中心。其次，激动剂配体优先与受体的G蛋白偶联高亲和力(HA)状态结合，从而提供了拮抗剂配体的几个优点。我们最近合成了几个11C标记的激动剂化合物，其特征是氮卓拉平结构骨架，该结构骨架显示了与恒河猴体内5-HT1A受体的特异性结合，该系列的先导化合物目前正在对人类进行评估。尽管这种化合物有许多优异的性质，但有一个限制是，初步数据表明，人类感兴趣的两个区域(杏仁核和海马体)的动力学过程很慢。18F的半衰期为110分钟，这将允许更长时间的合成和成像，从而促进动力学研究。因此，这两个问题需要开发18F标记的激动剂放射性示踪剂，通过保留在高要求的毒性和耐受性要求下幸存下来的氮卓拉西平结构骨架。此外，18F正电子能量是第一排正电子发射器中最低的，因此可以在最高分辨率下进行成像。我们设计了灵活的合成方案来合成四种18F标记的5-HT1a激动剂，它们都是氮卓拉平的衍生物。成年雄性大鼠的MicroPET扫描/常规动物解剖研究将用于初步确定放射性标记激动剂的血脑屏障渗透性和生物分布。然后，将评估合适的候选者作为潜在的5-HT1A受体的PET成像探针。在通过基线和区块研究以及代谢物分析的发展来确认狒狒特定的脑摄取之后，将根据测试/重测的重复性、可识别性和时间稳定性来选择最佳的建模方法。根据这一结果，临床研究的最佳候选者将被用于在体定量狒狒体内的HA5-HT1a受体。18F标记的激动剂PET示踪剂将为研究5-HT1a受体在神经精神障碍的病理生理学中的作用、预测抑郁症的治疗效果和5-HT1a靶向药物开发提供一个临床有用的工具。公共卫生相关性：5-羟色胺1A受体被认为在包括抑郁症、精神分裂症、阿尔茨海默病和焦虑在内的主要神经精神疾病中发挥关键作用。本研究旨在开发一种18F标记的激动剂正电子发射体层析探针，用于在体定量测定狒狒体内G蛋白偶联的高亲和力5-羟色胺1A受体。18F标记的激动剂PET示踪剂的成功开发将为研究5-羟色胺1A受体在神经精神障碍的病理生理学中的作用、预测严重抑郁症的治疗效果以及5-羟色胺1A受体靶向药物开发提供一个临床有用的工具。

DESCRIPTION (provided by applicant): This proposal aims to develop an 18F-labeled agonist PET probe for in vivo quantification of the G-protein coupled high affinity serotonin 1A (5-HT1A) receptors in baboon. We have two major motivations for developing an 18F labeled 5-HT1A receptor agonist radiotracer. First, we have previously shown that 5-HT1A receptors are abnormal in major depression and that elevated binding predicts response to antidepressants. One of the major impediments to using this technology in the clinic is the limited number of centers that can produce C-11 labeled radiotracers. The F-18 tracer can be shipped to multiple medical centers that are within a radius of 4 hours from the production site. Second, an agonist ligand binds preferentially to the G-protein coupled high affinity (HA) state of the receptor and thereby offers several advantages to an antagonist ligand. We have recently synthesized several 11C-labeled agonist compounds characterized by an azauracil structural skeleton that demonstrated specific binding to 5-HT1A receptors in baboon and the lead compound from the series is currently in evaluation in humans. Although this compound has many excellent properties, a limitation is that preliminary data suggest that the kinetics in two regions of interest (amygdala and hippocampus) is slow in humans. The 110-minute half-life of 18F would permit synthesis and imaging over longer duration, facilitating kinetic studies. Thus, these two issues necessitate the development of an 18F-labeled version of the agonist radiotracer by retaining the azauracil structural skeleton that survived the highly demanding toxicity and tolerance requirements. Additionally, the 18F positron energy is the lowest of the first row positron emitters and for this reason imaging can be potentially done at the highest resolution. We have designed flexible synthetic schemes for the synthesis of four 18F-labeled 5-HT1A agonists that are azauracil derivatives. MicroPET scans in adult male rats/ conventional animal dissection studies will be used for the preliminary determination of blood brain barrier permeability and biodistribution of the radiolabeled agonists. The suitable candidates will be then evaluated in baboon as potential PET imaging probes for 5-HT1A receptors. After confirming specific brain uptake in baboon by baseline and block studies, and development of metabolite analyses, the optimal modeling method will be selected on the basis of test/retest reproducibility, identifiability and time stability. Based on the results, the optimal candidate for clinical studies will be used for the in vivo quantification of HA 5-HT1A receptors in baboons. The 18F-labeled agonist PET tracer will provide a clinically useful tool to study the role of 5-HT1A receptors in the pathophysiology of neuropsychiatric disorders, for the prediction of treatment effectiveness in depression and for 5-HT1A targeted drug development. PUBLIC HEALTH RELEVANCE: The serotonin 1A receptor is implicated to play a critical role in major neuropsychiatric disorders including depression, schizophrenia, Alzheimer's disease and anxiety. This proposal aims to develop an 18F-labeled agonist PET probe for in vivo quantification of the G-protein coupled high affinity serotonin 1A receptors in baboon. The successful development of an 18F-labeled agonist PET tracer would provide a clinically useful tool to study the role of serotonin 1A receptors in the pathophysiology of neuropsychiatric disorders, for the prediction of treatment effectiveness in major depression and for the serotonin 1A receptor targeted drug development.