Development of Agonist PET Probes for Quantifying 5-HT1A Receptor Binding

用于定量 5-HT1A 受体结合的激动剂 PET 探针的开发

• 批准号: 7230138
• 负责人: MAJO VATTOLY JOSEPH
• 金额: $ 21.1万
• 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: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230138
• 关键词: Acute; Adult; Affinity; Agonist; Animals; Anxiety; Binding; Binding Sites; Biodistribution; Biological Assay; Blood - brain barrier anatomy; Bolus Infusion; Brain; Brain region; Citalopram; Clinical Research; Clinical Trials; Coupled; Development; Disease; Dissection; Evaluation; Functional disorder; GTP-Binding Proteins; Goals; Human; Image; In Vitro; Kinetics; Knowledge; Label; Lead; Life; Ligand Binding; Ligands; Measures; Mental Depression; Methods; Minor; Modeling; Molecular Conformation; National Institute of Mental Health; Numbers; Outcome Measure; Papio; Permeability; Pharmacotherapy; Population; Positron-Emission Tomography; Preclinical Drug Evaluation; Psychotropic Drugs; Publishing; Radiolabeled; Range; Rattus; Reporting; Reproducibility; Research Design; Research Personnel; Rodent; Role; Scanning; Scheme; Schizophrenia; Screening procedure; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Site; Specificity; Staging; Standards of Weights and Measures; Synapses; Synaptic Cleft; Testing; Time; Tissues; Tracer; Tryptophan; Variant; analog; base; design; drug development; imaging probe; in vivo; male; neuropsychiatry; nonhuman primate; programs; radioligand; radiotracer; receptor; receptor binding; research study; tool; uptake

DESCRIPTION (provided by applicant): This proposal aims to develop a specific 5-hydroxytryptamine-1A (5-HT1A) receptor agonist PET probe for in vivo quantification of high affinity (HA) state in nonhuman primates. The antagonist radiotracer [11C]WAY-100635 is the most commonly used 5-HT1A ligand for in vivo PET studies. However, antagonist ligands bind both to the HA and low affinity (LA) conformation of 5-HT1A receptor with equal affinity. In contrast, agonists bind preferentially to the HA state of the receptor which is coupled to G-protein, thereby providing a more meaningful functional measure of the 5-HT1A receptor. Estimation of the sensitivity of radioligand binding to competition by intrasynaptic serotonin would make it possible to compare serotonin levels after release or depletion in healthy and diseased populations. Moreover, the estimation of occupancy of, or effects on, HA sites of the 5-HT1A receptor are valuable tools for drug development. Compared to antagonist radioligands, an agonist PET radiotracer is expected to be more sensitive for these studies. To date, there are no published reports of a successful and selective 5-HT1A agonist PET radioligand in living brain. We have designed flexible synthetic schemes for concise access to 18F and 11C analogues of several recently identified highly selective 5-HT1A agonists. MicroPET scans in adult male rats/ conventional animal dissection studies will be used for the preliminary determination of the 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 and outcome measure will be determined by measuring 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 conformation of 5-HT1A receptors and tested in baboons to evaluate the sensitivity of agonist binding to changes in intra-synaptic serotonin levels. PET studies with 5-HT1A receptor agonist radiotracers are expected to offer new and more sensitive tools to study this important receptor and its role in the pathophysiology of depression, anxiety and other neuropsychiatric disorders and for 5-HT1A-targeted drug development.

描述（由申请人提供）：本提案旨在开发一种特异性5-羟色胺-1A（5-HT 1A）受体激动剂PET探针，用于非人灵长类动物体内高亲和力（HA）状态的定量。拮抗剂放射性示踪剂[11 C]WAY-100635是体内PET研究中最常用的5-HT 1A配体。然而，拮抗剂配体以相等的亲和力结合5-HT 1A受体的HA和低亲和力（LA）构象。相反，激动剂优先结合与G蛋白偶联的受体的HA状态，从而提供5-HT 1A受体的更有意义的功能测量。估计突触内5-羟色胺竞争的放射性配体结合的敏感性，将有可能比较健康和患病人群中释放或耗尽后的5-羟色胺水平。此外，估计5-HT 1A受体的HA位点的占用率或作用是药物开发的有价值的工具。与拮抗剂放射性配体相比，预期激动剂PET放射性示踪剂对这些研究更敏感。迄今为止，还没有公开的报道成功的和选择性的5-HT 1A激动剂PET放射性配体在活脑中。我们已经设计了灵活的合成方案，简明地获得18 F和11 C类似物的几个最近确定的高选择性5-HT 1A激动剂。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，将通过测量试验/复检重现性、可鉴别性和时间稳定性来确定最佳建模方法和结局指标。基于这些结果，临床研究的最佳候选物将用于体内定量5-HT 1A受体的HA构象，并在狒狒中进行测试，以评估激动剂结合对突触内5-羟色胺水平变化的敏感性。使用5-HT 1A受体激动剂放射性示踪剂的PET研究有望提供新的和更灵敏的工具，以研究这种重要的受体及其在抑郁症，焦虑症和其他神经精神疾病的病理生理学中的作用，并用于5-HT 1A靶向药物的开发。