Characterization Novel 5-HT1A Receptor Agonist PET

描述（由申请人提供）：这个修订的K 08指导临床科学家发展奖（MCSDA）的申请人正在寻求成为一个独立的研究者，专注于情绪障碍的神经生物学。未来五年的研究重点是扩展我在设计，执行和解释PET成像研究方面的技术专长，这些研究是针对大脑中的分子靶点开发的放射性配体。为了在分子成像领域实现独立性，因为它适用于精神疾病的研究，我将与我的申办者合作，他们在精神病患者人群中进行了许多PET放射性配体研究。该研究项目与指导和正式的教学课程一起提出，重点是将基本发现转化为早期临床试验，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。本申请中提出的研究的具体目标是表征[11 C]-MPT，我们的新5-羟色胺1A（5-HT 1A）受体激动剂放射性配体在狒狒中，然后在人脑中。我们将检验[11 C]-MPT对狒狒和人类脑突触内5-HT水平变化敏感的假设（通过色氨酸耗竭和静脉注射西酞普兰）。我们还将检验以下假设：拮抗剂（羰基-[11 C]WAY-100635）与激动剂（[11 C]-MPT）受体结合的比值大于1，因此可以估计低与高激动剂亲和力5-HT 1A结合位点的比值。该比率是多巴胺能传递功效的重要决定因素，其可在各种精神疾病中改变。5-HT 1A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体的开发和表征将有助于研究5-HT 1A受体在这些疾病的神经生物学中的作用，其通过定量处于高激动剂亲和力状态的5-HT 1A受体，所述5-HT 1A受体可以经由G蛋白偶联至第二信使系统，并且通过定量响应于疾病和健康中的治疗性和/或实验性干预的突触内5-羟色胺。目前没有5-HT 1A激动剂放射性配体可用于体内PET成像。在转化研究领域培训研究科学家，如这里提出的，可以加速新PET示踪剂的临床研究转化。

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.