New molecular magnetic resonance imaging (mMRI) contrast agents for imaging of Cathepsin B

用于组织蛋白酶 B 成像的新型分子磁共振成像 (mMRI) 造影剂

• 批准号: 351032-2008
• 负责人: Bedell, Barry
• 金额: $ 5.88万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=431363
• 关键词: New; molecular; magnetic; resonance; imaging

Cathepsin B (CatB), a cysteine protease, is known to be associated with numerous pathological conditions of the central nervous system (CNS), including brain tumours (e.g. gliomas) and Alzheimer's disease (AD). In gliomas, CatB plays a major role in tumour invasion through degradation of the extracellular matrix. As such, a large number of CatB inhibitors are actively being developed as anti-cancer agents, including targeted therapies based on enzyme-activated prodrug strategies. In AD, CatB is thought to play anti-amyloidogenic and neuroprotective functions. As such, pharmacological agents which increase the expression of CatB have the potential to counteract AD neuropathology. In both glioma and AD, measuring the expression and/or activity of CatB is crucial for the proper assessment the therapeutic efficacy of new agents. While traditional measures of changes in enzyme expression/activity in response to therapeutic intervention, such as enzyme histochemistry and immunohistochemistry on tissue sections, are feasible for animal models, these methods are not practical in human subjects. As such, methods to monitor enzyme expression/activity in a non-invasive fashion are required. In this proposal, we plan to develop novel CatB-activated molecular MRI probes and to subsequently evaluate these probes in rodent models of glioma and AD. This proposed project is truly multi-disciplinary and will seamlessly combine the expertise from Dr. Scott Bohle's lab (McGill Department of Chemistry) for the design, synthesis, and chemical characterization of the probes, Dr. Edith Hamel's lab (Department of Neurology and Neurosurgery, Montreal Neurological Institute/McGill University) for the ex vivo evaluation of probe activity as well as in vivo evaluation in mouse models of AD, and Dr. Barry Bedell's lab (Small Animal Imaging Lab, Montreal Neurological Institute/McGill University) for the development of MRI techniques for CatB probe evaluation in rodent models of glioma and AD.

众所周知，一种半胱氨酸蛋白酶的组织蛋白酶B（CATB）与中枢神经系统（CNS）的许多病理状况有关，包括脑肿瘤（例如神经胶质瘤）和阿尔茨海默氏病（AD）。在神经胶质瘤中，CATB通过降解细胞外基质在肿瘤侵袭中起主要作用。因此，大量的CATB抑制剂正在积极开发为抗癌药物，包括基于酶激活的前药策略的有针对性疗法。在AD中，CATB被认为具有抗淀粉样生殖和神经保护功能。因此，增加CATB表达的药理学剂具有抵消AD神经病理学的潜力。在神经胶质瘤和AD中，测量CATB的表达和/或活性对于正确评估新药物的治疗功效至关重要。尽管响应治疗干预的酶表达/活性变化的传统措施，例如组织切片的酶组织化学和免疫组织化学对于动物模型是可行的，但这些方法在人类受试者中是不可行的。因此，需要以非侵入性方式监测酶表达/活性的方法。 在此提案中，我们计划开发新型CATB激活的分子MRI探针，并随后在神经胶质瘤和AD的啮齿动物模型中评估这些探针。 This proposed project is truly multi-disciplinary and will seamlessly combine the expertise from Dr. Scott Bohle's lab (McGill Department of Chemistry) for the design, synthesis, and chemical characterization of the probes, Dr. Edith Hamel's lab (Department of Neurology and Neurosurgery, Montreal Neurological Institute/McGill University) for the ex vivo evaluation of probe activity as well as in vivo evaluation in mouse models of AD和Barry Bedell博士的实验室（蒙特利尔神经学院/麦吉尔大学的小动物成像实验室），用于开发用于神经胶质瘤和AD啮齿动物模型中CATB探针评估的MRI技术。