Indole Glyoxylamides Peripheral Benzodiazepine Receptor

吲哚乙醛酰胺外周苯二氮卓受体

• 批准号: 7110892
• 负责人: GILLES D TAMAGNAN
• 金额: $ 24.92万
• 依托单位: MOLECULAR NEUROIMAGING, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110892
• 关键词: Macaca mulatta; amides; benzodiazepine receptor; bioimaging /biomedical imaging; blood brain barrier; brain imaging /visualization /scanning; chemical synthesis; heterocyclic compounds; hydropathy; indoles; pharmacokinetics; positron emission tomography; radiopharmacology; radiotracer; receptor binding; single photon emission computed tomography; technology /technique development

The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of the peripheral benzodiazepine receptor (PBR ) in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radio-tracer binding specifically to PBR would be of great utility in diagnosis, monitoring treatment, and etiological research of neuropsychiatric disorders such as brain damage, neurodegenerative diseases, anxiety and stress disorders. The PBR is thought to be associated with many biological functions, including the regulation of cellular proliferation, immunomodulation, porphyrin transport, heme biosynthesis, anion transport, regulation of steroidogenesis, and apoptosis. For example, increases in PBR have been observed in brain tissue from patients with HIV/AIDS, Alzheimer's disease, Huntington's disease, multiple sclerosis, and gliosis. A PET study in patients with AIDS showed increased cortical and subcortical PBR receptor binding, supporting the role of glial cell activation in HIV patients with dementia. This study highlights the limitations of current radioligands used and points out the need to further optimize quantitation of PBR. We found that certain indole glyoxylamide derivatives showed nanomolar affinity to PBR. However, brain uptake of two of them labeled with 123I was low in nonhuman primate. Key questions posed by these results are: a) Can PBR affinity and selectivity be increased while reducing lipophilicity with different heterocyclic substituents? And b) are the homogenate binding results applicable to in vivo uptake and distribution? In this application we propose to test the following hypotheses: 1) N,N-dialkyl indolylglyoxylamides with appropriately functionalized heterocyclic substituents on the 2-position of indole will favor binding to PBR relative to CBR; and 2) introduction of these heteroaromatic rings will alter the lipophilicity of our compounds so as to have lower nonspecific binding and higher brain uptake. We will synthesize a series of N,N-dialkyl-2-heterocyclic substituted indolylglyoxylamides. The candidates with binding affinities below 10 nM for PBR and selectivity vis-a-vis CBR above 100 will be radiolabeled with F-18 or I-123 and their lipophilicity (log D) will be measured. In vivo binding will be measured in nonhuman primates by imaging regional brain distribution of the radio-tracer under control conditions and with specific pharmacological challenges. Correlation of log D, in vitro affinity, and in vivo selectivity will be evaluated. At the conclusion of this project period, we expect to have identified a radioligand suitable for imaging the PBR in NeuroAIDS, dementia and other diseases.

本研究项目的目标是定义配体的结构和放射性标记，以便通过正电子（PET）或单光子（SPECT）发射断层扫描的外部成像来定量测量活脑中的外周苯二氮卓受体（PBR）。特异结合PBR的放射性示踪剂将在脑损伤、神经退行性疾病、焦虑和应激障碍等神经精神疾病的诊断、监测治疗和病因学研究中发挥重要作用。PBR被认为与许多生物学功能有关，包括细胞增殖调节、免疫调节、卟啉运输、血红素生物合成、阴离子运输、类固醇生成调节和细胞凋亡。例如，在艾滋病毒/艾滋病、阿尔茨海默病、亨廷顿病、多发性硬化症和神经胶质瘤患者的脑组织中观察到PBR的增加。一项针对艾滋病患者的PET研究显示，皮层和皮层下PBR受体结合增加，支持神经胶质细胞激活在艾滋病患者伴痴呆中的作用。本研究强调了目前使用的放射性配体的局限性，并指出需要进一步优化PBR的定量。我们发现某些吲哚乙醛酰胺衍生物对PBR具有纳米摩尔亲和力。然而，在非人灵长类动物中，其中两种标记为123I的大脑摄取较低。这些结果提出的关键问题是：a)不同的杂环取代基是否可以在降低亲脂性的同时提高PBR的亲和力和选择性？b)匀浆结合结果是否适用于体内摄取和分布？在本应用中，我们提出验证以下假设：1)相对于CBR，在吲哚2位上具有适当官能化杂环取代基的N，N-二烷基吲哚基乙醛酰胺更有利于与PBR结合；2)杂芳环的引入将改变化合物的亲脂性，从而降低非特异性结合，提高脑摄取。