New approaches to carbon-11 labeled carbonyl and thiocarbonyl groups for positron emission tomography radiotracer synthesis and development

用于正电子发射断层扫描放射性示踪剂合成和开发的碳 11 标记羰基和硫代羰基的新方法

• 批准号: RGPIN-2017-06167
• 负责人: Rotstein, Benjamin
• 金额: $ 4.81万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744328
• 关键词: New; approaches; carbon; 11; labeled

Carbon-11 is a short-lived radioactive isotope with a half-life of 20.3 minutes, and which has important applications for biochemistry research, drug development, and diagnostic medical imaging. Since carbon atoms form the backbone of all organic compounds and nearly all biomolecules, drugs, and imaging agents, carbon-11 is the most versatile isotope for preparing labeled analogues of these for imaging without changing their behaviour in living systems. To synthesize imaging agents with carbon-11, chemical transformations need to be performed in rapid succession with high efficiency under strictly controlled conditions to ensure reproducible results and the safety and utility of products. Our research program develops improved chemical methods with carbon-11 and new imaging agents using this isotope. Specifically, we believe that methods for incorporating high oxidation state carbon-11 labels into molecules from its production form as carbon dioxide and similar derivatives such as carbon monoxide and cyanide will greatly expand the synthetic armament for this isotope and directly lead to novel and improved radiopharmaceuticals available to power molecular imaging.Our program is specifically targeting synthesis of radiolabeled amides, which are very common chemical bonds found in drugs and proteins. We will develop new methods to prepare these bonds in ways that are specifically useful for radiochemistry, including discovery of amide syntheses using transition metal catalysts and precursors for carbon-carbon-11 bond formation. Such particularly selective methods will enable labeling of more complex molecules as well as combinatorial syntheses. These advances will lead to a more efficient strategy for tracer development, since we can start with simpler chemical inputs to make complex labeled molecules. Finally, we can also prepare new labeled molecules beyond amides, and pursue our long-term goal of being able to envision synthesis of imaging agents bearing any proposed organic structure, and developing methods to make them on a practical scale, suitable for in vivo imaging.As part of this research, students will undergo a strong foundation of training in organic chemistry in addition to highly specialized training in radiochemistry with short-lived isotopes and radiopharmaceutical method development, ideally suited for future careers in the medicinal chemistry, radiopharmacy, and imaging sectors. Our lab is an interdisciplinary training setting located at the University of Ottawa Heart Institute, and trainees will have daily interaction with basic science researchers in physics, biochemistry, and microbiology, as well as engineering and medical researchers and practitioners. We will also avidly pursue technology transfer and commercialization of intellectual property resulting from our discoveries.

碳-11是一种半衰期为20.3分钟的短寿命放射性同位素，在生物化学研究、药物开发和诊断医学成像方面具有重要应用。由于碳原子形成所有有机化合物和几乎所有生物分子、药物和成像剂的骨架，碳-11是制备这些标记类似物用于成像而不改变其在生命系统中的行为的最通用的同位素。为了合成具有碳-11的成像剂，需要在严格控制的条件下以高效率快速连续地进行化学转化，以确保可重复的结果以及产品的安全性和实用性。我们的研究项目开发了碳-11的改进化学方法和使用这种同位素的新成像剂。具体而言，我们相信，将高氧化态碳-11标记物从其生产形式（如二氧化碳和类似衍生物，如一氧化碳和氰化物）掺入分子中的方法将极大地扩展该同位素的合成武器，并直接导致可用于为分子成像提供动力的新型和改进的放射性药物。这是药物和蛋白质中常见的化学键。我们将开发新的方法，以特别适用于放射化学的方式制备这些键，包括发现使用过渡金属催化剂和碳-碳-11键形成前体的酰胺合成。这种特别选择性的方法将使得能够标记更复杂的分子以及组合合成。这些进展将导致更有效的示踪剂开发策略，因为我们可以从更简单的化学输入开始制造复杂的标记分子。最后，我们还可以制备酰胺以外的新标记分子，并追求我们的长期目标，即能够设想合成具有任何拟议有机结构的成像剂，并开发方法使其在实用规模上适用于体内成像。学生将经历在有机化学培训的坚实基础，除了在放射化学高度专业化的培训，活性同位素和放射性药物方法开发，非常适合未来在药物化学，放射性药物和成像部门的职业生涯。我们的实验室是位于渥太华大学心脏研究所的跨学科培训环境，学员将与物理学，生物化学和微生物学的基础科学研究人员以及工程和医学研究人员和从业人员进行日常互动。我们还将积极寻求技术转让和我们的发现所产生的知识产权的商业化。