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 postinjection. 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 two 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.