Bridging the Gap between Discovery and Clinical Reality in Radiopharmaceuticals: A Translational Science Perspective on Safety, Efficacy, and Manufacturability.

The clinical success of recent radioligand therapies has renewed interest in radiopharmaceutical therapy (RPT). Despite hundreds of clinical trials over the past decade, only two current-generation systemic radioligand therapies (Lutathera and Pluvicto) have received FDA approval. This bottleneck reflects the treatment of RPTs as conventional targeted therapies, overlooking the interplay among radionuclide physics, carrier pharmacokinetics, tumor biology, and manufacturing constraints. We examine translational pitfalls across the RPT pipelinetarget discovery, chemical design, radiolabeling, preclinical evaluation, and scalable manufacturingand propose a holistic framework. We argue that the field should move from empirical, static modifications toward active spatiotemporal control, including covalent "bind-and-lock" mechanisms and cleavable linkers to separate efficacy from systemic toxicity. We also discuss challenges of high-energy α-emitters, physical nanoconfinement as an alternative to chelation for recoil-sensitive systems, site-specific conjugation for Chemistry, Manufacturing, and Controls (CMC), "true matched" isotopic pairs, cellular-level microdosimetry, and AI-driven design for manufacturability.