The development of novel methods to efficiently synthesise new radiotracers is an active area of research in nuclear medicine. One major advancement is the development of the
aluminium-[18F]fluoride ([18F]AlF) method, which has enabled facile and efficient radiofluorination reactions. The [18F]AlF2+ complex, described as a pseudo-radiometal,
combines the convenience of radiometal-based synthetic approaches with the favourable
decay characteristics of fluorine-18. These advantages have led to the widespread
implementation of the [18F]AlF method for producing new radiotracers, with an array of clinical trials already being reported. This thesis aims to further expand on the applications of the [18F]AlF method and develop new approaches to allow its incorporation into biomolecules.
Firstly, the utility of the [18F]AlF method in enabling facile 18F-labelling of microbubbles was developed to enable their whole-body distributions to be tracked. An [18F]AlF-labelled tetrazine was synthesised in excellent radiochemical yield and used to radiolabel trans-cyclooctene-functionalised microbubbles via the efficient inverse-electron-demand Diels-Alder (IEDDA) reaction. To further improve the accessibility of 18F-labelled microbubbles, a kit-based approach was successfully developed. This approach allows microbubbles to be radiolabelled with minimal radiochemical expertise, which potentially facilitates the development of new lipid-based microbubble formulations. In addition, the [18F]AlF-labelled microbubbles were also successfully applied for evaluating the effects ultrasound-mediated microbubble destruction and sonoporation in enhancing the delivery of radioactivity to tumours, further demonstrating the utility of the [18F]AlF method in enabling different biological phenomena to be studied.
This thesis also investigated the potential to improve on the current [18F]AlF-labelling
methodologies. To facilitate [18F]AlF-labelling under milder conditions, the development of new chelators was undertaken. Whilst initial studies using aluminium-salen complexes showed their potential for 18F-labelling, conclusive evidence on the formation of an Al-F bond was not obtained, necessitating further optimisation of the ligand structure and fluorination conditions.
Finally, the ability to site-selectively radiolabel biomolecules by [18F]AlF was explored using
the π-clamp-mediated cysteine conjugation method. Two approaches were developed: (i) a
prosthetic group approach, and (ii) a direct [18F]AlF-labelling approach. Both approaches
demonstrated the utility of the [18F]AlF method to be used for site-selectively radiolabelling
octreotate as the model peptide, providing the potential for translation to larger biomolecules.
In summary, the work presented herein provides an extension to the current toolkit of
radiolabelling microbubbles and biomolecules using the [18F]AlF method, which ultimately seeks to expand on the available strategies for producing new radiotracers.