Probes for imaging enzyme activity

背景癌症从原发肿瘤扩散到远处，这一过程称为转移，是90%患者死亡的原因。癌症进展的关键步骤是局部环境的重塑，肿瘤开始以该局部环境侵入。这种重塑被认为主要是通过称为蛋白酶的分子机器发生的，这些酶消化肿瘤环境，为癌细胞入侵提供允许的空间。然而，帮助癌症扩散的确切机制和特定蛋白酶还不清楚。我们建议设计和开发新的化学试剂，可以使用正电子发射断层扫描（PET）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。PET产生的图像代表人体内的代谢信息。它需要注射微量的放射性PET示踪剂，使用回旋加速器设施中产生的同位素，这些同位素将在代谢活性组织中积累。我们将设计和制备新的PET示踪剂，这些示踪剂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，在该计划的过程中取得的进展可用于PET成像癌症以外的疾病中的蛋白酶活性，包括心血管疾病，关节炎和动脉粥样硬化。冲击新的和改进的PET分子成像方法可以用作识别帮助癌症扩散的蛋白酶的重要研究工具。 一旦确定特定的蛋白酶促进肿瘤侵袭，它将成为高度优先的治疗靶点。 最终，这项工作也可能导致一种临床测试，能够同时检测癌症（诊断）和评估所发现肿瘤的侵袭性（预后）。培训学生的就业机会。在2007年提交给美国国家科学院的一份报告中，PET放射化学培训人员的全球短缺已被确定为对PET成像科学的威胁。从那时起，回旋加速器设施数量的不断增加加剧了这种短缺。实际上，加拿大8个新的回旋加速器场址现已投入运作，其中包括不列颠哥伦比亚癌症、萨斯卡通、温尼伯、雷霆湾、大学卫生网、桑尼布鲁克研究所、伦敦和哈利法克斯的设施。此外，现有设施在舍布鲁克、汉密尔顿、蒙特利尔和埃德蒙顿安装了更多的回旋加速器。该提案将有助于培训下一代放射化学家，从而使快速扩大的加拿大网站能够以其所需的能力运作，并为从NSERC赠款中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.**