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: $ 2.4万
• 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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684879
• 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是一种短寿命放射性同位素，半衰期为20.3分钟，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。由于碳原子构成所有有机化合物以及几乎所有生物分子、药物和成像剂的主链，因此碳 11 是最通用的同位素，可用于制备这些标记类似物以进行成像，而无需改变它们在生命系统中的行为。为了用碳11合成显像剂，需要在严格控制的条件下快速、连续、高效地进行化学转化，以确保结果的可重复性以及产品的安全性和实用性。我们的研究项目开发了改进的碳 11 化学方法以及使用该同位素的新型显像剂。具体来说，我们相信，将高氧化态碳 11 标记结合到二氧化碳和类似衍生物（例如一氧化碳和氰化物）的分子中的方法将极大地扩展该同位素的合成武器，并直接导致新型和改进的放射性药物可用于驱动分子成像。******我们的计划专门针对放射性标记酰胺的合成，这是药物和蛋白质中非常常见的化学键。我们将开发新方法来以专门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能够标记更复杂的分子以及组合合成。这些进步将为示踪剂开发带来更有效的策略，因为我们可以从更简单的化学输入开始来制造复杂的标记分子。最后，我们还可以制备除酰胺之外的新标记分子，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显像剂，并开发方法以实际规模生产它们，适合体内成像.******作为这项研究的一部分，除了短寿命同位素放射化学和放射性药物方法开发方面的高度专业化培训外，学生还将接受有机化学方面的坚实基础培训，非常适合未来在医学领域的职业生涯化学、放射药剂学和成像领域。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机构，学员将与物理、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。我们还将热切地追求我们的发现所产生的技术转让和知识产权的商业化。