Development of agonist PET tracers for quantifying 5HT2AR

开发用于定量 5HT2AR 的激动剂 PET 示踪剂

• 批准号: 8268355
• 负责人: JAYA PRABHAKARAN
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268355
• 关键词: Adult; Affinity; Agonist; Anatomy; Antidepressive Agents; Antipsychotic Agents; Autopsy; Autoradiography; Back; Binding; Binding Sites; Biodistribution; Brain; Brain region; Comparative Study; Data; Development; Disease; Dose; Evaluation; Functional disorder; GTP-Binding Proteins; Goals; High Pressure Liquid Chromatography; Human; Image; In Vitro; Incubated; Investigation; Ketanserin; Kinetics; Label; Laboratories; Lead; Letters; Ligands; Measurement; Measures; Mental Depression; Metabolism; Methods; Modeling; Molecular Conformation; National Institute of Mental Health; Nature; Neurodegenerative Disorders; Neurotransmitters; Outcome; Papio; Penetration; Permeability; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Preclinical Drug Evaluation; Prefrontal Cortex; Preparation; Psychotropic Drugs; Qualifying; Radioactivity; Radiolabeled; Rattus; Reproducibility; Research Personnel; Role; Route; Scanning; Schizophrenia; Second-Generation Antidepressive Agents; Services; Site; Slide; Specificity; Study models; Synapses; System; Testing; Therapeutic; Time; Tracer; Validation; analog; atypical antipsychotic; drug development; flasks; imaging probe; in vivo; innovation; interest; neuropsychiatry; pre-clinical; programs; radioligand; radiotracer; receptor; receptor binding; research study; suicidal behavior; suicide victim; therapeutic target; tool; uptake

DESCRIPTION (provided by applicant): Serotonin2A receptors (5HT2AR) have significant role in the pathophysiology of schizophrenia, depression and neurodegenerative diseases and are also targets for atypical antipsychotics and antidepressants. Agonist tracers allow measurement of the high affinity conformation of receptors that can be bound to G-proteins and are potentially sensitive to intra-synaptic levels of endogenous neurotransmitters. In vitro autoradiography studies performed in our laboratories using the agonist radiotracer [125I]LSD indicated a significant increase in 5HT2R binding in suicide victims compared to matched controls, whereas, studies by others and us using antagonist radioligands were unable to derive the precise nature of alterations of the receptor binding. Therefore, developing an agonist radiotracer may offer new more sensitive and accurate tool in investigating the role of 5HT2AR systems in neuropsychiatric disorders, and to develop innovative therapeutics. A combination of the antagonist and agonist PET data would allow separate quantification in the high and low affinity conformational states. We performed in vivo quantification of 5HT2AR binding by PET using the antagonist radioligand [11C] M100, 907 in baboons and human. However, the potential of agonist radioligands developed so far for studying 5HT2AR is limited due to poor subtype selectivity and nonspecific binding. Our objective is therefore, to develop a specific agonist radiotracer as a probe for imaging 5HT2AR in the functionally active state using PET. In vitro binding studies of [3H]INBMeO a potent agonist 5HT2AR ligand (1, 5HT2AR Ki = 0.044 nM, EC50 = 0.44 nM, Emax = 81%) demonstrated specific binding in postmortem human brain. INBMeO has superior selectivity over a number of receptors, particularly to the other 5HT2 subtypes. We synthesized [11C]INBMeO in high yield and specific activity and our preliminary investigation in baboon using PET indicated the tracer penetrates the BBB and distributes preferentially to 5HT2AR enriched brain regions. Our goal is to establish specificity by pretreatment studies with a known 5HT2AR agonist and antagonist, test retest experiments and tracer kinetic modeling to understand the potential of [11C]1 for imaging high affinity site 5HT2AR. A new set of analogues 2, 3 & 4 will be synthesized in parallel, screened for 5HT2AR affinity, functional activity, BBB penetration and distribution in rats and the ligand that indicate the best binding will serve as back up if [11C]1 is proven suboptimal. We are also proposing a comparative study of the binding of the most successful agonist ligand and the antagonist [11C]M100907 binding in baboon brain to evaluate the total receptor concentration and the concentration of HA conformation of 5HT2AR. At the end of the proposed studies we anticipate to have an agonist PET tracer as potential tool for in vivo human studies of the functional high affinity state of 5HT2AR and to demonstrate in vivo target engagement for preclinical validation of therapeutic targets.

描述（由申请人提供）：血清素2a受体（5HT2AR）在精神分裂症，抑郁和神经退行性疾病的病理生理学中具有重要作用，并且也是非典型抗精神病药和抗抑郁药的靶标。激动剂示踪剂允许测量受体的高亲和力构象，这些受体可能与G蛋白结合，并可能对内源性神经递质的突触内敏感。使用激动剂放射性示踪剂[125i] LSD在我们的实验室进行的体外自身自显影研究表明，与匹配的对照相比，自杀受害者的5HT2R结合显着增加受体结合。因此，开发激动剂放射性示例可能会在研究5HT2AR系统在神经精神疾病中的作用以及开发创新的治疗剂时提供更灵敏和准确的工具。拮抗剂和激动剂宠物数据的结合将允许在高和低亲和力构象状态下单独定量。我们使用蝙蝠和人类中的拮抗剂放射性物体[11C] M100、907对PET进行了5HT2AR结合的体内定量。然而，由于亚型选择性差和非特异性结合，迄今为止，用于研究5HT2AR的激动剂放射线的潜力受到限制。因此，我们的目标是开发一种特定的激动剂放射性示踪剂，作为使用PET在功能活性状态中成像5HT2AR成像的探针。 [3H] InbMeo的体外结合研究有效的激动剂5HT2AR配体（1，5HT2AR KI = 0.044 nm，EC50 = 0.44 nm，EMAX = 81％）在邮政邮政脑中表现出特定的结合。 INBMEO比许多受体具有较高的选择性，尤其是对其他5HT2亚型。我们以高产量和特定活性合成[11C] Inbmeo，我们在狒狒中使用PET进行了初步研究，表明示踪剂穿透了BBB并优先分配到5HT2AR富集的大脑区域。我们的目标是通过使用已知的5HT2AR激动剂和拮抗剂，测试重新测试实验和示踪剂动力学建模来建立特异性，以了解[11C] 1对成像高亲和力位点5HT2AR的潜力。一组新的类似物2、3和4将并行合成，筛选为5HT2AR亲和力，功能活动，BBB穿透和分布在大鼠中，以及指示最佳结合的配体，如果证明[11C] 1被证明是备份次优。我们还提出了对狒狒大脑中最成功的激动剂配体和拮抗剂[11C] M100907结合的结合的比较研究，以评估总受体浓度和5HT2AR HA构象的浓度。在拟议的研究结束时，我们预计将有一个激动剂宠物示踪剂作为5HT2AR功能性高亲和力体内人类研究的潜在工具，并证明体内靶标参与临床上的治疗靶标。