Recent Advances in Targeting Nuclear Molecular Imaging Driven by Tetrazine Bioorthogonal Chemistry

Molecular imaging techniques apply sophisticated technologies to monitor, directly or indirectly, the spatiotemporal distribution of molecular or cellular processes for biomedical, diagnostic, or therapeutic purposes. For example, Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging, the most representative modalities of molecular imaging, enable earlier and more accurate diagnosis of cancer and cardiovascular diseases. New possibilities for noninvasive molecular imaging in vivo have emerged with advances in bioorthogonal chemistry. For example, tetrazine-related Inverse Electron Demand Diels-Alder (IEDDA) reactions can rapidly generate short-lived radioisotope probes in vivo that provide strong contrast for SPECT and PET. Here, we review pretargeting strategies for molecular imaging and novel radiotracers synthesized via tetrazine bioorthogonal chemistry. We systematically describe advances in direct radiolabeling and pretargeting approaches in SPECT and PET using metal and nonmetal radioisotopes based on tetrazine bioorthogonal reactions, and we discuss prospects for the future of such contrast agents.