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

开发用于定量 5-HT1A 受体的 18F 标记激动剂 PET 探针

• 批准号: 7826699
• 负责人: MAJO VATTOLY JOSEPH
• 金额: $ 24.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826699
• 关键词: Adult; Affinity; Agonist; Alzheimer' s Disease; Amygdaloid structure; Animals; Antidepressive Agents; Anxiety; Binding; Binding Sites; Biodistribution; Blood - brain barrier anatomy; Brain; Clinic; Clinical Research; Coupled; Data; Development; Disease; Dissection; Evaluation; Functional disorder; GTP-Binding Proteins; Goals; Half-Life; Hippocampus (Brain); Hour; Human; Image; Kinetics; Label; Lead; Life; Ligand Binding; Ligands; Major Depressive Disorder; Measures; Medical center; Mental Depression; Methods; Modeling; Molecular Conformation; Motivation; National Institute of Mental Health; Papio; Permeability; Play; Positron; Positron-Emission Tomography; Preclinical Drug Evaluation; Production; Property; Psychotropic Drugs; Radial; Radiolabeled; Rattus; Reproducibility; Resolution; Role; Scanning; Scheme; Schizophrenia; Screening procedure; Series; Serotonin; Serotonin Receptor 5-HT1A; Shipping; Ships; Site; Skeleton; Specificity; Technology; Testing; Time; Tissues; Toxic effect; Tracer; Treatment Effectiveness; Triazines; azauracil; base; design; drug development; flexibility; imaging probe; in vivo; interest; male; neuropsychiatry; programs; public health relevance; radioligand; radiotracer; receptor; response; tool; uptake

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.

描述（由申请人提供）：本提案旨在开发一种18F标记的激动剂PET探针，用于狒狒体内G蛋白偶联高亲和力5-羟色胺1A（5-HT 1A）受体的体内定量。我们有两个主要的动机，开发18 F标记的5-HT 1A受体激动剂放射性示踪剂。首先，我们以前已经表明，5-HT 1A受体在重度抑郁症中是异常的，并且升高的结合预测对抗抑郁药的反应。在临床上使用这项技术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示踪剂可以运送到距离生产现场4小时半径内的多个医疗中心。第二，激动剂配体优先结合受体的G蛋白偶联高亲和力（HA）状态，从而为拮抗剂配体提供几个优点。我们最近合成了几种11 C标记的激动剂化合物，其特征在于azauracil结构骨架，其表现出与狒狒中的5-HT 1A受体特异性结合，并且该系列的先导化合物目前正在人体中进行评估。尽管这种化合物具有许多优异的特性，但其局限性在于，初步数据表明，在人类中，两个感兴趣的区域（杏仁核和海马体）的动力学是缓慢的。18F的110分钟半衰期将允许在更长的持续时间内合成和成像，促进动力学研究。因此，这两个问题需要通过保留氮尿嘧啶结构骨架来开发激动剂放射性示踪剂的18F标记形式，所述氮尿嘧啶结构骨架在高度苛刻的毒性和耐受性要求下存活。此外，18F正电子能量是第一行正电子发射器中最低的，并且由于这个原因，成像可以潜在地以最高分辨率进行。我们设计了灵活的合成方案，用于合成四种18F标记的5-HT 1A激动剂，它们是氮尿嘧啶衍生物。成年雄性大鼠/常规动物解剖研究中的MicroPET扫描将用于初步测定血脑屏障通透性和放射性标记激动剂的生物分布。然后将在狒狒中评价合适的候选物作为5-HT 1A受体的潜在PET成像探针。在通过基线和区组研究确认狒狒的特定脑摄取以及代谢物分析开发后，将根据试验/复检重现性、可鉴别性和时间稳定性选择最佳建模方法。基于结果，临床研究的最佳候选物将用于狒狒中HA 5-HT 1A受体的体内定量。18F标记的激动剂PET示踪剂将提供一种临床有用的工具，用于研究5-HT 1A受体在神经精神疾病的病理生理学中的作用，用于预测抑郁症的治疗效果和5-HT 1A靶向药物的开发。公共卫生相关性：5-羟色胺1A受体在包括抑郁症、精神分裂症、阿尔茨海默病和焦虑症在内的主要神经精神障碍中起关键作用。本研究旨在开发一种18F标记的激动剂PET探针，用于狒狒体内G蛋白偶联高亲和力5-羟色胺1A受体的定量。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受体在神经精神疾病的病理生理学中的作用、预测重度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临床有用的工具。