Development of Copper(II)- Mediated Methods for PET Imaging Applications

PET;Copper;Fluorination;Chemistry;Science;Chemistry

Makaravage, KatarinaWolfe, John P ;

University of Michigan

关键词: PET;    Copper;    Fluorination;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/149863/kjmak_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Positron emission tomography (PET) is an imaging technique that uses a radioactive small molecule to monitor biological processes. As the radioactive molecule moves throughout the body, it emits positrons that allow it to be tracked using a PET scan. Key information can be learned during this scan, including how the molecule engages the target of interest, ability to cross the blood-brain barrier, how quickly it is cleared from the body, etc. As PET imaging becomes more prevalent, the need for more diverse tracers increases. This thesis describes several new methods for forming C–18F and C–11C bonds that have and will continue to be utilized for the synthesis of new PET imaging tracers. Chapter 1 describes the importance of fluorinated arenes and their importance in PET imaging. Current methods for radiolabeling these substrates are discussed. Challenges for developing PET methodologies and labeling molecules with other radioactive isotopes are discussed.Chapter 2 focuses on the development of copper-mediated [18F]radiofluorination methodologies using aryl boron acids and arylstannanes derivatives as precursors. Both methods have wide substrate scopes and were fully automated to provide clinical doses of [18F]MPP-F.Chapter 3 details the development of a copper-mediated [11C]radiocyanation method that is applicable to various aryl boron and arylstannanes derivatives. This methodology was utilized to produce [11C]perampanel and [11C]LY2795050 on a clinical scale. [11C]LY2795050 was used for a non-human primate imaging study and is currently undergoing clinical trials. Chapter 4 focuses on the development of a copper-mediated directed C(sp2)–H [18F]radiofluorination method. Chapters 2 and 3 used pre-functionalized precursors, which can hinder application to more complicated substrates. The development of a C–H activation method that uses a removable directing group could be highly advantageous for molecules in clinical trials. Chapter 5 details three incomplete projects: (1) [18F]radiofluorination of aryl iodides, (2) directed fluorination of other removable directing groups, and (3) improved [18F]radiofluorination of [18F]4F-MHPG. Preliminary results and future directions are discussed.This dissertation describes new methodologies that have been developed and how they have been applied in our lab and others. New methodologies to form C–18F and C–11C bonds will become more pertinent as the field of PET continues to grow and new targets are identified. We believe the methods discussed herein will serve an important role for helping the PET community diagnose and monitor diseases earlier and more effectively than alternative imaging techniques.