Development of the First Aliphatic ¹⁸ F-Labeled Tetrazine Suitable for Pretargeted PET Imaging—Expanding the Bioorthogonal Tool Box

Abstract

Pretargeted imaging of nanomedicines have attracted considerable interest because it has the potential to increase imaging contrast while reducing radiation burden to healthy tissue. Currently, the tetrazine ligation is the fastest bioorthogonal reaction for this strategy and, consequently, the state-of-art choice for <i>in vivo</i> chemistry. We have recently identified key properties for tetrazines in pretargeting. We have also developed a method to ¹⁸F-label reactive tetrazines using an aliphatic nucleophilic substitution strategy. Here, we combined this knowledge and developed an ¹⁸F-labeled tetrazine for pretargeted imaging. In order to develop this ligand, a small SAR study was performed. The most promising compound was selected for labeling and subsequent positron-emission-tomography <i>in vivo</i> imaging. Radiolabeling was achieved in satisfactory yields, molar activities, and high radiochemical purities. [¹⁸F]<b>15</b> displayed favorable pharmacokinetics and remarkable target-to-background ratios-as early as 1 h post injection. We believe that this agent could be a promising candidate for translation into clinical studies.