Characterization Novel 5-HT1A Receptor Agonist PET

新型 5-HT1A 受体激动剂 PET 表征

• 批准号: 7149597
• 负责人: MATE ISTVAN MILAK
• 金额: $ 17.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-03 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149597
• 关键词: antidepressants; baboons; binding sites; bioimaging /biomedical imaging; cell surface receptors; citalopram; clinical research; drug screening /evaluation; human subject; mathematical model; neuropharmacology; pharmacokinetics; positron emission tomography; psychopharmacology; radiopharmacology; radiotracer; receptor binding; receptor sensitivity; serotonin receptor; synaptic vesicles; tryptophan

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.

描述（由申请人提供）：本次修订后的 K08 指导临床科学家发展奖 (MCSDA) 的申请人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者。未来五年的研究计划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业知识，以及针对大脑分子靶标开发的放射性配体。为了在分子成像领域实现独立，因为它适用于精神疾病研究，我将与我的资助者合作，他在精神病患者群体中进行了许多 PET 放射性配体研究。与指导和正式教学课程一起提出的研究项目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。本申请中提出的研究的具体目标是表征狒狒和人脑中的新血清素 1A (5-HT1A) 受体激动剂放射性配体 [11C]-MPT。我们将检验以下假设：[11C]-MPT 对狒狒和人类大脑突触内 5-HT 水平的变化敏感（通过色氨酸消耗和静脉注射西酞普兰）。我们还将测试以下假设：拮抗剂 (羰基-[11C]WAY-100635) 与激动剂 ([11C]-MPT) 受体结合的比率大于 1，因此低与高激动剂亲和力 5-HT1A 结合的比率可以估计站点。该比率是血清素传递功效的重要决定因素，可能在各种精神疾病中发生改变。 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体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，方法是量化高激动剂亲和力状态下的 5-HT1A 受体，该受体可以通过 G 蛋白与第二信使系统偶联，并通过量化突触内血清素来响应疾病和健康的治疗和/或实验干预。目前没有可用于体内 PET 成像的 5-HT1A 激动剂放射性配体。在本文提出的转化研究领域培训研究科学家可以加速新 PET 示踪剂向临床研究的转化。