Probes for imaging enzyme activity

背景资料。在90%的患者中，癌症从原发肿瘤扩散到远处的过程称为转移，是死亡的原因。癌症进展的关键一步是肿瘤开始侵袭的局部环境的重塑。这种重塑被认为主要是通过被称为蛋白酶的分子机器发生的，这种酶消化肿瘤环境，为癌细胞入侵提供了一个允许的空间。然而，帮助癌症扩散的确切机制和特定的蛋白水解酶还不是很清楚。我们建议设计和开发新的化学试剂，利用正电子发射断层扫描(PET)来揭示在肿瘤和肿瘤环境中工作的特定蛋白酶的活性。 建议的工作。宠物制作的图片代表了人体内的新陈代谢信息。它需要注入微量的放射性PET示踪剂，使用回旋加速器设施中产生的同位素，这些同位素将积累在代谢活跃的组织中。我们将设计和制备新的PET示踪剂，这种示踪剂可以被蛋白酶激活，并在侵袭性乳腺癌的肿瘤环境中积累。重要的是，在该计划过程中取得的进展可用于对癌症以外的疾病(包括心血管疾病、关节炎和动脉粥样硬化)的蛋白水解酶活性进行PET成像。 冲击力。新的和改进的PET分子成像方法可以作为一种重要的研究工具来识别有助于癌症扩散的蛋白酶。一旦一种特定的蛋白酶被确定为促进肿瘤侵袭，它将成为高度优先的治疗靶点。最终，这项工作还可能导致一种临床测试，能够同时检测癌症(诊断)和评估发现的肿瘤的侵袭性(预后)。 培养学生的就业机会。在2007年提交给美国国家科学院的一份报告中，全球接受过PET放射化学培训的人员短缺被确定为对PET成像科学的威胁。自那以后，回旋加速器设施的数量不断扩大，加剧了短缺。事实上，8个新的加拿大回旋加速器设施，包括位于卑诗省癌症、萨斯卡通、温尼伯、桑德贝、大学健康网络、桑尼布鲁克研究所、伦敦和哈利法克斯的设施现已投入使用。此外，现有设施还在舍布鲁克、汉密尔顿、蒙特利尔和埃德蒙顿安装了额外的回旋加速器。这项提议将有助于培训下一代放射化学家，从而使迅速扩大的加拿大站点能够以其所需的能力运行，并为从NSERC补助金培训的学生提供极好的职业机会。

Background. The spread of cancer from a primary tumor to a distant location, a process termed metastasis, is the cause of death in 90% of patients. A critical step in the progression of cancer is the remodeling of the local environment with which tumours begin to invade. This remodeling is thought to occur primarily through molecular machines called proteases, enzymes that digest the tumour environment providing a permissive space for cancer cells to invade. However, the exact mechanisms and the specific proteases that help cancers spread are not well understood. We propose to design and develop new chemical agents that can reveal the activity of specific proteases operating in the tumour and the tumour environment using positron emission tomography (PET). Proposed Work. PET produces pictures that represent metabolic information within a person's body. It requires the injection of a minute amount of a radioactive PET tracer, using isotopes produced in a cyclotron facility, that will accumulate in metabolically active tissues. We will design and prepare new PET tracers that become activated by proteases and accumulate in the tumour environment of aggressive breast cancer. Importantly, the advancements made over the course of this program may be used to PET image protease activity in diseases other than cancer including cardiovascular disease, arthritis and atherosclerosis. Impact. New and improved PET molecular imaging methods could be used as an important research tool for identifying proteases that help cancer spread. Once a specific protease has been determined to promote tumour invasion, it would become a high priority therapeutic target. Eventually, this work could also lead to a clinical test capable of simultaneously detecting cancer (diagnosis) and assessing the aggressiveness of the discovered tumour (prognosis). Career Opportunities of Students Trained. A global shortage of people trained in PET radiochemistry has been identified as a threat to PET imaging science in a report submitted to the U.S. National Academy of Sciences in 2007. Since then, the shortage has been exacerbated by the expanding number of cyclotron facilities. Indeed, 8 new Canadian cyclotron sites including facilities in BC Cancer, Saskatoon, Winnipeg, Thunder Bay, University Health Network, Sunnybrook Research Institute, London and Halifax are now operational. In addition, established facilities installed additional cyclotrons in Sherbrooke, Hamilton, Montreal and Edmonton. This proposal will help train the next generation of radiochemists thus allowing the rapidly expanding Canadian sites to operate at their desired capacity and provide excellent careers opportunities for students trained from this NSERC grant.