Development of Group II mGluR Radiotracers

II 类 mGluR 放射性示踪剂的开发

• 批准号: 7099989
• 负责人: RIKKI Noel WATERHOUSE
• 金额: $ 36.17万
• 依托单位: MERCK AND COMPANY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099989
• 关键词: Academia; Acute; Affinity; Agonist; Alzheimer' s Disease; American; Anxiety Disorders; Applications Grants; Behavioral; Brain; Chemicals; Chemistry; Chronic; Clinical Trials; Collaborations; Condition; Data; Data Analyses; Development; Disease; Dose; Drug Delivery Systems; Drug Design; Family; Female; Fostering; Glutamates; Goals; Guanosine Monophosphate; Health; Human; Human Cloning; Human Volunteers; Image; Imaging Techniques; Industry; Institutes; Investigational Drugs; Label; Lead; Ligands; Mediating; Mediation; Metabotropic Glutamate Receptors; Methodology; Methods; Mission; National Institute of Mental Health; Nature; Nerve Degeneration; Neurodegenerative Disorders; Organ; Patients; Pharmaceutical Preparations; Phase; Physicians; Positron-Emission Tomography; Protocols documentation; Psychotic Disorders; Publishing; Radiation; Radioactive; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research Ethics Committees; Research Personnel; Rodent; Role; Safety; Schizophrenia; Site; Specificity; Staging; Standards of Weights and Measures; Structure; System; Testing; Time; Toxic effect; Toxicity Tests; Toxicology; Tracer; United States Food and Drug Administration; Universities; base; dosimetry; genotoxicity; healthy volunteer; human study; human subject; in vivo; interest; male; neuropsychiatry; nonhuman primate; pharmacokinetic model; pre-clinical; programs; radiochemical; radioligand; radiotracer; receptor; repository; tool; uptake; volunteer; whole body imaging

DESCRIPTION (provided by applicant): The goal of this collaboration between academia and industry is to produce a safe, publicly owned radiopharmaceutical for imaging group Il metabotropic glutamate receptors (mGluRs) with positron emission tomography (PET). New glutamatergic drugs are fast being developed to treat neurodegenerative disorders, anxiety disorders, and psychoses, some of which are major American health problems. However, no effective radioligands for imaging this family of receptors in vivo have been reported. Central to this application is an ongoing strong collaborative effort between researchers at Eli Lilly, Inc. and Columbia University, including a focused project plan that fully utilizes the unique strengths of both institutes as is geared towards radiotracer development. To solidify the successful development of effective mGluR tracers for in vivo PET imaging, this project centers on antagonist-based radiotracers, including molecules that possess higher affinity and much less hydrophilicity than known mGluR agonists such as LY354740 and LY379268. Target candidate radioligands with potentially higher affinity than the group IT mGluR antagonist LY341495, but containing groups readily amenable to labeling with PET radionuclides, will therefore be synthesized and highly evaluated. Researchers at Columbia University will carry out organic and radiochemical syntheses and perform in vivo characterization of new tracers, including rodent, non-human primate and human PET studies. Eli Lilly will provide structure/activity data and expert chemistry advice, characterization of ligands against cloned human mGluRs, and toxicity testing performed to industry and FDA standards. The R33 phase includes the filing of an IND application, and characterization of the tracer via human PET imaging, including whole body dosimetry, test-retest analysis and blocking studies. Successful completion of this project will provide an effective method to non-invasively probe the status and function of mGluRs in humans by PET imaging techniques. Radiolabeled mGluR antagonists will additionally facilitate in vivo dose-receptor occupancy determinations of new drugs targeted to these sites via PET methods. The tools and methods developed will be made readily available to interested researchers, and federal grant applications will subsequently be submitted to explore the role of mGluRs in certain neuropsychiatric and neurodegenerative disorders by PET imaging.

描述（由申请人提供）：学术界和工业界之间的合作目标是生产一种安全的、公共拥有的放射性药物，用于通过正电子发射断层扫描（PET）对 II 族代谢型谷氨酸受体（mGluR）进行成像。新的谷氨酸能药物正在迅速开发，用于治疗神经退行性疾病、焦虑症和精神病，其中一些是美国的主要健康问题。然而，尚未报道用于体内成像该受体家族的有效放射性配体。该应用的核心是礼来公司和哥伦比亚大学研究人员之间持续的强有力的合作努力，包括一个重点项目计划，该计划充分利用两个研究所的独特优势，以开发放射性示踪剂。为了巩固用于体内 PET 成像的有效 mGluR 示踪剂的成功开发，该项目以基于拮抗剂的放射性示踪剂为中心，包括比已知的 mGluR 激动剂（如 LY354740 和 LY379268）具有更高亲和力和更低亲水性的分子。因此，将合成并高度评估目标候选放射性配体，其亲和力可能高于 IT mGluR 拮抗剂 LY341495 组，但含有易于用 PET 放射性核素标记的基团。哥伦比亚大学的研究人员将进行有机和放射化学合成，并对新示踪剂进行体内表征，包括啮齿动物、非人类灵长类动物和人类 PET 研究。礼来公司将提供结构/活性数据和专家化学建议、克隆人 mGluR 配体的表征以及按照行业和 FDA 标准进行的毒性测试。 R33 阶段包括提交 IND 申请，以及通过人体 PET 成像对示踪剂进行表征，包括全身剂量测定、重测分析和阻断研究。该项目的成功完成将为通过PET成像技术非侵入性地探测人类mGluRs的状态和功能提供一种有效的方法。放射性标记的 mGluR 拮抗剂还将有助于通过 PET 方法确定针对这些位点的新药的体内剂量受体占用率。开发的工具和方法将可供感兴趣的研究人员使用，随后将提交联邦拨款申请，以通过 PET 成像探索 mGluR 在某些神经精神和神经退行性疾病中的作用。