Covalent chemistry-driven innovations in radiopharmaceutical design and delivery

Radiopharmaceuticals play a central role in molecular imaging and targeted radionuclide therapy, yet their clinical performance is often hindered by rapid clearance, poor tumor retention, and off-target accumulation. Recent advances have highlighted covalent strategies as promising solutions to enhance the localization and efficacy of radiopharmaceuticals. This review outlines two complementary approaches: direct covalent targeting, which enables irreversible probe anchoring through proximity-driven or environment-responsive reactions, and pretargeting, which employs bioorthogonal chemistry to separate targeting and radiolabeling phases. By focusing on covalent chemistry and rational design principles, this review provides a mechanistic and forward-looking framework for engineering next-generation radiopharmaceuticals with enhanced pharmacodynamic profiles and clinical translation potential.