Development of PET Radioligands for NMDA Receptors

NMDA 受体 PET 放射性配体的开发

• 批准号: 6688942
• 负责人: RIKKI Noel WATERHOUSE
• 金额: $ 16.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688942
• 关键词: NMDA receptors; bioimaging /biomedical imaging; blood brain barrier; brain disorder diagnosis; chemical kinetics; diagnosis design /evaluation; guanidines; isoflurane; laboratory rat; membrane channels; noninvasive diagnosis; phencyclidine; positron emission tomography; protein structure function; radiotracer

DESCRIPTION (provided by applicant): Alterations in normal NMDA channel subunit composition and function are implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. Binding of NMDA ligands to succinct modulatory sites located on the outside of or within the ion channel serves to modulate behavioral and neurochemical responses. For this proposal, the NMDA/PCP site has been specifically chosen as an imaging target since the involvement of this site in cognitive and neurodegenerative processes and psychotic behaviors is well documented. The development of effective PET tracers for the study of NMDA receptors is critical to providing much needed tools for understanding of the etiology and improving the clinical management of disorders thought to involve the associated ion channel. The PCP site is located inside the ion channel. Effective PCP site tracers will bind their target selectively during the active and "open" state of the ion channel. Therefore, an effective PCP site tracer would serve as a non-invasive in vivo tool to report on the functional state of the channel. In addition to providing information regarding channel activation, these tracers would also be able to monitor the density of these sites. To identity effective PCP site tracers, novel substituted N, N'-alkyl-diphenyl guanidines will be synthesized and evaluated. Candidate ligands possessing high affinity, selectivity, and appropriate lipophilicity will be radiolabeled and further characterized in in vitro assays and in vivo models. In addition to aspects of radiotracer design synthesis, specific issues regarding appropriate methods to evaluate the new tracers for effective labeling of the ion channel in vivo will be addressed. To supplement the more classical methods of PET radiotracer evaluation, we will adopt an ex vivo method for determining the degree of in vivo saturable binding that occurs with these ligands. While well-established cell membrane assays will be used, an additional modified in vitro assay will allow us to probe the nature of binding of tracers to closed and open states of the channel. The use of these models will provide additional information to assist in the development of clinically useful PCP site radioligands. The data obtained will be pivotal for the design of studies to non-invasively assess NMDA receptor function and will identify suitable radiotracers and provide preliminary data to support future grant submissions.

描述（由申请人提供）：正常NMDA通道亚基组成和功能的改变与某些神经和神经精神疾病的病理生理学有关，例如帕金森病、亨廷顿舞蹈病、精神分裂症、酗酒和中风。 NMDA 配体与位于离子通道外部或内部的简洁调节位点的结合可调节行为和神经化学反应。对于该提案，NMDA/PCP 位点被专门选择作为成像目标，因为该位点参与认知和神经退行性过程以及精神病行为已有充分记录。开发用于 NMDA 受体研究的有效 PET 示踪剂对于提供急需的工具来了解病因和改善与相关离子通道有关的疾病的临床管理至关重要。 PCP 位点位于离子通道内。有效的 PCP 位点示踪剂将在离子通道的活跃和“开放”状态期间选择性地结合其目标。因此，有效的 PCP 位点示踪剂将作为一种非侵入性体内工具来报告通道的功能状态。除了提供有关通道激活的信息外，这些示踪剂还能够监测这些站点的密度。为了识别有效的 PCP 位点示踪剂，将合成并评估新型取代的 N,N'-烷基-二苯基胍。具有高亲和力、选择性和适当亲脂性的候选配体将被放射性标记，并在体外测定和体内模型中进一步表征。 除了放射性示踪剂设计合成方面之外，还将解决有关评估新示踪剂以有效标记体内离子通道的适当方法的具体问题。为了补充 PET 放射性示踪剂评估的更经典方法，我们将采用离体方法来确定与这些配体发生的体内饱和结合程度。虽然将使用成熟的细胞膜测定，但额外的改良体外测定将使我们能够探测示踪剂与通道关闭和开放状态结合的性质。这些模型的使用将提供额外的信息，以协助开发临床上有用的 PCP 站点放射性配体。获得的数据对于非侵入性评估 NMDA 受体功能的研究设计至关重要，并将确定合适的放射性示踪剂并提供初步数据以支持未来的拨款申请。