Characterization of a Novel 5-HT1A Receptor Agonist PET Ligand

描述(由申请者提供)：本次修订的K08临床科学家导师发展奖(MCSDA)的申请者正在寻求成为一名专注于情绪障碍神经生物学的独立研究员。计划在未来五年内开展的研究重点是扩大我在设计、执行和解释PET成像研究方面的技术专长，这些研究是为大脑中的分子靶点开发的放射性配基。为了在应用于精神疾病研究的分子成像领域实现独立性，我将与我的赞助人合作，他在精神疾病患者群体中进行了许多PET放射配基研究。提出的研究项目以及指导和正式的教学课程侧重于将基本发现转化为早期临床测试，包括将新合成的分子成像探针通过监管障碍转移到早期临床研究所需的专业知识。在这项应用中提出的研究的具体目标是表征我们的新的5-HT1A(5-HT1A)受体激动剂放射性配基[11C]-MPT在恒河猴和人脑中的特性。我们将测试假设，即[11C]-MPT将敏感于脑内突触内5-羟色胺水平的变化(通过色氨酸耗竭和静脉注射西酞普兰)。我们还将检验这样的假设，即拮抗剂(羰基-[11C]Way-100635)与激动剂([11C]-mpt)受体结合的比率大于1，因此可以估计激动剂亲和力低与高的5-HT1a结合位点的比率。这一比例是5-羟色胺能传递效率的重要决定因素，在各种精神疾病中可能会改变。5-HT1a受体与抑郁、焦虑、精神病和记忆障碍有关。成功的激动剂放射性配基的开发和表征将有助于研究5-HT1A受体在这些疾病的神经生物学中的作用，方法是量化处于高激动剂亲和力状态的5-HT1A受体，该受体可以通过G蛋白偶联到第二信使系统，并通过定量突触内的5-羟色胺来响应疾病和健康的治疗和/或实验干预。目前还没有5-HT1A激动剂放射性配基可用于活体PET成像。在转译研究领域对研究科学家进行培训，例如这里提出的，可以加速将新的PET示踪剂转化为临床研究。

DESCRIPTION (provided by applicant): The applicant of this revised K08 Mentored Clinical Scientist Development Award (MCSDA) is seeking to become an independent investigator focusing on the neurobiology of mood disorders. Research proposed for the next five years focuses on expanding my technical expertise in designing, executing and interpreting PET imaging research with radioligands developed for molecular targets in the brain. In order to achieve independence in the field of molecular imaging as it applies to the study of mental illness, I will work with my Sponsor who conducts many PET radioligand studies in psychiatric patient populations. The research project proposed together with mentoring and formal didactic coursework focuses on translation of basic discoveries to early phase clinical testing, including the expertise needed to move newly synthesized molecular imaging probes through the regulatory barriers to early phase clinical studies. The specific objective of the research proposed in this application is to characterize [11C]-MPT, our new serotonin 1A (5-HT1A) receptor agonist radioligand in baboon and then in human brain. We will test the hypothesis that [11C]-MPT will be sensitive to changes in brain intra-synaptic 5-HT levels in baboon and human (by tryptophan depletion and iv citalopram administration). We will also test the hypothesis that the ratio of antagonist (carbonyl-[11C]WAY-100635) to agonist ([11C]-MPT) receptor binding is greater than one and therefore the ratio of low versus high agonist affinity 5-HT1A binding sites can be estimated. This ratio is an important determinant of serotonergic transmission efficacy that may be altered in a variety of psychiatric conditions. The 5-HT1A receptors have been implicated in depression, anxiety, psychosis and memory disturbances. The development and characterization of a successful agonist radioligand would assist research into the role of the 5-HT1A receptor in the neurobiology of these illnesses by quantifying 5-HT1A receptors in the high agonist affinity state that can couple via G proteins to the second messenger system, and by quantifying intra-synaptic serotonin in response to therapeutic and/or experimental interventions in disease and health. There is currently no 5- HT1A agonist radioligand available for in vivo PET imaging. Training research scientists in areas of translational research such as proposed here can accelerate the translation of new PET tracers to clinical research.