Development of Ga-labelled ultrasound microbubbles for whole-body PET imaging.

Microbubble (MB) contrast agents have revolutionalised the way ultrasound (US) imaging can be used clinically and pre-clinically. Contrast-enhanced US offers improvements in soft-tissue contrast, as well as the ability to visualise disease processes at the molecular level. However, its inability to provide whole-body imaging can hamper the development of new MB formulations. Herein, we describe a fast and efficient method for achieving Ga-labelling of MBs after a direct comparison of two different strategies. The optimised approach produces Ga-labelled MBs in good yields through the bioorthogonal inverse-electron-demand Diel-Alder reaction between a -cyclooctene-modified phospholipid and a new tetrazine-bearing HBED-CC chelator. The ability to noninvasively study the whole-body distribution of Ga-labelled MBs was demonstrated using positron emission tomography (PET). This method could be broadly applicable to other phospholipid-based formulations, providing accessible solutions for tracking of MBs.