A reagent-based approach for [18F]trifluoromethoxylation

Lead Research Organisation: University of Oxford
Department Name: Synthesis for Biology & Medicine CDT

Abstract

Fluorinated molecules remain valuable to the pharmaceutical and agrochemical industries because of their unique properties. This has led to the development of a wide array of methodologies for their synthesis, allowing access to an ever-growing number of fluorine-containing bioactive molecules. Alongside this, the applicability of fluorinated molecules enriched with the unnatural isotope of fluorine, F-18, in the molecular imaging technique positron emission tomography (PET) is well established in the clinic. Advances in radiofluorination have facilitated the labelling of some fluorinated motifs with F-18 in generally applicable methods, while other fluorine-containing groups remain challenging to label and are therefore underexplored in the development of new radiotracers.
One such functionality is the trifluoromethoxy group (OCF3), which exhibits several special properties, making its incorporation into bioactive molecules advantageous. For example, this group exhibits superior thermodynamic and metabolic stability, compared with other fluoroalkyl substituents, such as fluoromethoxy (-OCH2F) and fluoromethyl groups (-CH2F). However, there are significant challenges associated with the installation of this motif. The trifluoromethoxide (OCF3-) anion is unstable, so its use as a nucleophilic OCF3 source is restricted. Novel reagents, able to circumvent this problem by the controlled release of OCF3- in situ, have been disclosed and these strategies have facilitated access to OCF3-containing molecules.
However, there exists only a single report of the radiolabelling of the OCF3 group, which involves a silver(I) mediated halogen exchange from bromodifluoromethyl aryl ether precursors. This method was able to deliver the [18F]OCF3 group in good radiochemical yield, but this corresponded to a low molar activity, limiting its utility as an OCF3 radiolabelling method.
This state of play prompted us to consider the development of new approaches to the [18F]OCF3 group. We aim to access this motif via a reagent-based strategy that will release [18F]OCF3- in a controlled manner. To achieve this, extensive experimentation on the analogous system using F-19 will be prioritised initially. This will allow for the identification of a suitable reagent and conditions for its synthesis and reaction with various commercially available precursors. At this point, after the preparation of various analogues and investigation of their reactivity in model reactions, a lead compound will be selected for further study. A robust radiosynthesis of the reagent from cyclotron-generated [18F]fluoride will be devised and implemented, followed by a selective activation of this reagent under optimised reaction conditions to yield [18F]trifluoromethoxylated products in good radiochemical yield and molar activity. We aim to radiolabel bioactive molecules to demonstrate the applicability of our method to complex molecules and future radiotracer candidates.
This project aligns well with the EPSRC's strategies and falls within the EPSRC 'Physical Sciences' research area, with direct relevance to the 'Healthcare Technologies' area.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R513295/1 01/10/2018 30/09/2023
2285020 Studentship EP/R513295/1 01/10/2019 30/03/2023 Joseph Ford