Exploring Structural Parameters for Pretargeting Radioligand Optimization

Pretargeting offers a way to enhance target specificity while reducing off-target radiation dose to healthy tissue during payload delivery. We recently reported the development of an 18F-based pretargeting strategy predicated on the inverse electron demand Diels-Alder reaction as well as the use of this approach to visualize pancreatic tumor tissue in vivo as early as 1 h post-injection. Herein, we report a comprehensive structure-pharmacokinetic relationship study of a library of 25 novel radioligands that aims to identify radiotracers with optimal pharmacokinetic and dosimetric properties. This investigation revealed key relationships between molecular structure and in vivo behavior and produced 2 lead candidates exhibiting rapid tumor targeting with high target-to-background activity concentration ratios at early time points. We believe this knowledge to be of high value for the design and clinical translation of next-generation pretargeting agents for the diagnosis and treatment of disease.