Figure 1.

Illustration of conventional nuclear imaging compared to pretargeted nuclear imaging of a tumor targeting nanomedicine using the tetrazine ligation. Here, the nanomedicine, which acts as the primary targeting agent, is a polymer modified with trans-cyclooctene (TCO), and the secondary imaging agent is a radiolabeled 1,2,4,5-tetrazine (Tz). In conventional nuclear imaging, the nanomedicine is radiolabeled (yellow box), administered, and allowed to circulate for days to achieve tumor accumulation and sufficient systemic clearance for imaging (usually a time frame of 22–72 h). In pretargeted nuclear imaging, the TCO-modified primary targeting agent (blue box) is administered and allowed to circulate until tumor accumulation and sufficient systemic clearance has been achieved. Thereafter, the radiolabeled Tz (pink box) is administered, imaging is performed within the first few hours as the bioorthogonal reaction between TCO and Tz, and the excretion of Tz proceeds rapidly.