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 patient is pretreated with a biomolecule that has high specificity for its target. A radiolabelled second component is then administered to the patient 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.