The inverse electron demand Diels-Alder cycloaddition with carbon-11 and fluorine-18: A gateway to pretargeted imaging across the blood-brain barrier.

There is increased focus on developing tools to image large biomolecules, such as antibodies, within the brain using positron emission tomography (PET). The inverse electron demand Diels-Alder cycloaddition (IEDDA) reaction has offered the greatest prospect of achieving such a feat and has gained much interest over the past decade. The fast reaction kinetics of the IEDDA reaction opens up the possibility of utilising a pretargeted approach, whereby the subject is pretreated with a biomolecule that has high specificity for its target. A radiolabelled second component is then administered to the subject, enabling the biomolecule to be visualised by PET. However, for this to become common practice, there is a need for the development of either radiolabelled trans-cyclooctenes (TCOs) or tetrazines that can cross the blood-brain barrier (BBB). This review highlights the advancements in the development of both radiolabelled TCOs and tetrazines, which have been radiolabelled with either carbon-11 or fluorine-18 and show promise or have been evaluated for use in pretargeted PET imaging across the BBB.