Micro-flow photosynthesis of new dienophiles for inverse-electron-demand Diels-Alder reactions. Potential applications for pretargeted PET imaging.

Pretargeted PET imaging has emerged as an effective two-step approach that combines the superior affinity and selectivity of antibodies with the rapid pharmacokinetics and favorable dosimetry of smaller molecules radiolabeled with short-lived radionuclides. This approach can be based on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between tetrazines and -cyclooctene (TCO) derivatives. We aimed to develop new [F]TCO-dienophiles with high reactivity for IEDDA reactions, and favorable stability and pharmacokinetics. New dienophiles were synthesized using an innovative micro-flow photochemistry process, and their reaction kinetics with a tetrazine were determined. stability and biodistribution of the most promising F-radiolabeled-TCO-derivative () was investigated, and its potential for pretargeted PET imaging was assessed in tumor-bearing mice. We demonstrated that is a suitable dienophile for IEDDA reactions and for pretargeting applications.