High Yield Synthesis of Positron Emission Tomography Ligands for Metabotropic Glutamate Receptor Imaging

Authors

Saraanne E. Hitchcock, University of Nebraska-LincolnFollow

Date of this Version

8-2011

Comments

A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Master of Science, Major: Chemistry, Under the Supervision of Professor Stephen G. DiMagno. Lincoln, Nebraska: August 2011

Copyright 2011 Saraanne E. Hitchcock

Abstract

Positron Emission Tomography (PET) is a powerful and non-invasive imaging technique used for human and animal organ imaging. Currently, the market for PET is project to reach $5.4 billion per year by 2015.5 This research focuses on the direct incorporation of [18F]-fluoride into PET ligands. The widespread use of PET imaging is currently frustrated, in part, by the lack of efficient fluorination chemistry.

Glutamate, one of the 20 most abundant naturally occurring amino acids, serves as a neurotransmitter in the central nervous system. Glutamate functions in this capacity by binding to ionotropic and metabotropic receptors. Metabotropic receptors are Gcoupled proteins that are involved in many disorders such as Parkinson’s disease, anxiety, depression and addiction. This research focuses on the preparation of PET ligands for the mGluR5 subtype receptor.

3-fluoro-5-(pyridin-2-ylethynyl)benzonitrile (PEB) and 3-fluoro-5-((6-methylpyridin-2-yl)ethynyl)benzonitrile (MPEB) are the two of the drugs of interest for this research. Previously reported ¹⁸F-radiolabeling techniques for the preparation of compounds of this class involved a halogenated precursor with KF in DMSO and using microwave heating. This strategy yielded approximately 4% RCY (“RCY” in this thesis refers to decay-corrected yield). We chose this class of compounds as a target because it provides an opportunity to develop synthetic [¹⁸F]-fluoride methodology to make this drug widely available for neuroscience and neuromedicine.

This method developed here for fluorination of aromatic rings can be expanded to achieve incorporation of ¹⁸F into aromatic amino acids. Amino acids have been known to target tumor cells specifically. In conclusion, this newly developed fluorination methodology opens a door to a variety of compounds that can be used for PET imaging studies.

Advisor: Stephen G. DiMagno