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

碳-11是一种半衰期为20.3分钟的短命放射性同位素，在生物化学研究、药物开发和诊断医学成像等方面有着重要的应用。由于碳原子构成了所有有机化合物和几乎所有生物分子、药物和显像剂的主干，碳-11是用途最广泛的同位素，用于制备这些标记的类似物用于成像，而不会改变它们在生命系统中的行为。为了合成碳-11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，以确保结果的重现性和产品的安全性和实用性。我们的研究项目用碳-11开发了改进的化学方法，并使用这种同位素开发了新的显像剂。具体地说，我们认为，将高氧化态碳-11标记与二氧化碳以及一氧化碳和氰化物等类似衍生物结合到分子中的方法将极大地扩大这种同位素的合成武器，并直接导致可用于分子成像的新型和改进的放射性药物。 我们的计划专门针对放射性标记酰胺的合成，这是在药物和蛋白质中发现的非常常见的化学键。我们将开发新的方法来制备这些键，这些方法对放射化学特别有用，包括发现使用过渡金属催化剂的酰胺合成和用于碳-碳-11键形成的前体。这种特别选择性的方法将使标记更复杂的分子以及组合合成成为可能。这些进展将导致示踪剂开发的更有效的策略，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，我们还可以在酰胺之外制备新的标记分子，并追求我们的长期目标，即能够设想合成具有任何提议的有机结构的显像剂，并开发方法使其达到实用规模，适合体内成像。 作为这项研究的一部分，学生将接受坚实的有机化学基础培训，此外还将接受短期同位素放射化学和放射性制药方法开发方面的高度专业化培训，非常适合未来在药物化学、放射性制药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方面的基础科学研究人员以及工程和医学研究人员和从业者进行日常互动。我们还将积极推动我们的发现所产生的技术转让和知识产权商业化。

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.