Reimagining chelator design to unlock the next generation of targeted radiopharmaceuticals

The Department of Health and Human Services National Institutes of Health Office of the Director awarded $855,000 to UT-Battelle LLC (Oak Ridge National Laboratory) on September 1, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to develop structurally expanded bifunctional chelators for targeted radiopharmaceuticals in cancer diagnosis and treatment.

The award funds research to redesign chelating frameworks that bind radiometal cations and attach targeting vectors to cancer cells. The current chelator paradigm, unchanged for two decades, supports only single radiocation-single chelator-single targeting vector configurations and cannot accommodate the diverse chemical properties and composition of emerging medical radionuclides. The research will explore a three-pronged design strategy incorporating anion recognition, cooperativity, and multiplicity to overcome obstacles in aqueous speciation, stability, and specific activity that have left many radionuclides stranded in the "valley of death" between production and clinical implementation.

Performance takes place in Oak Ridge, Tennessee. The period of performance runs from September 1, 2026, through August 31, 2031. The award is classified as a Project Grant and supports an early-career research program as a New Innovator proposal.

Abstract

This new innovator proposal supports the launch of an early-career research program focused on reimagining the design of bifunctional chelators to unlock the next-generation of targeted radiopharmaceuticals for cancer diagnosis and treatment. The mounting interest in targeted radiopharmaceuticals, coupled with advances in radioisotope production, has given rise to an arsenal of emerging medical radionuclides spanning the periodic table. These radionuclides possess attractive nuclear decay properties and half-lives that could render them extremely valuable for imaging and treating a wider range of cancers. Yet, many of them remain untapped-stuck in the "valley of death" between production and clinical implementation-because of a lack of bifunctional chelators that can deliver them effectively to cancer cells. The design of bifunctional chelators has remained unchanged over the last two decades, with most chelators only able to bind a single radiometal cation via strong dative bonding interactions and attach to a single targeting vector. This paradigm is incompatible with the diverse chemical properties, purity, and composition of many emerging radionuclides. The overarching goal of this proposal is to develop structurally expanded chelating frameworks to buck the current "one radiocation-one chelator-one targeting vector" paradigm that is holding back many radionuclides. Because there is no one-size-fits-all approach to satisfy every emerging radionuclide, we will explore a three-pronged design strategy to achieve our goal. Namely, we hypothesize that structurally expanded chelating frameworks incorporating the fundamental principles of anion recognition, cooperativity, and multiplicity can be designed to surmount the major obstacles in medical radionuclide advancement related to complex aqueous speciation, poor stability, and low specific activity, respectively. Notably, these challenges are pervasive across a wide range of emerging radionuclides with strong potential to advance the field of cancer imaging and therapy. Our approach integrates organic synthesis, radiochemistry, in vitro experiments, and collaborative in vivo studies to evaluate the coordination chemistry of novel bifunctional constructs with representative emerging radionuclides and establish their ability to improve radionuclide delivery to cancer cells in comparison to conventional chelators. By directly addressing the key barriers limiting the use of emerging radionuclides, this research will deliver broadly enabling chelation strategies that open new frontiers in radiopharmaceutical science and precision oncology.