Sunday, June 1, 2025
6/1/2025
Enabling Molecular Approaches for Copper-Based Radiopharmaceuticals - As access to cyclotron sources have become more readily available, radioisotopes of copper (e.g., 64Cu: β+ = 653 keV, t1/2 = 12.7 h; 67Cu: β- = 141 keV, t1/2 = 61.9 h) have received increasing attention for imaging and therapy due to their sensitivity, resolution, and half-life compared to other radionuclei (e.g., 11C, 18F, 68Ga). The overwhelming majority of active 64Cu or 67Cu clinical trials, as well as the FDA approved 64Cu radiopharmaceutical, [64Cu][Cu(DOTATATE)] (DetectnetTM), employ bifunctional chelators (BFCs) based on macrocyclic polyaminocarboxylates. These BFC form thermodynamically and kinetically stable copper complexes and display promising performance in head-to-head clinical trials; however, applications of Cu-based radiopharmaceuticals have been limited by their in vivo stability (i.e., reduced imaging sensitivity and increased off-target radiation to organs and tissues). Despite significant clinical attention and >25 years of BFC development, fundamental knowledge underpinning improvement-driven design (i.e., structure, reactivity, mechanisms of metal-loss) remain limited. In this research project, we will overcome longstanding challenges in the development of copper-based radiopharmaceuticals through advancing the designs of BFC with exceptional in vivo kinetic stability. Our mechanistically-driven study employs an interdisciplinary approach that embeds a tight feedback loop between novel BFC design, in vitro, and in vivo studies capable of enabling target-driven improvements in radiopharmaceutical performance. This approach will develop quantitative structure-function relationships bridging molecular-level BFC attributes with radiopharmaceutical properties and performance in vivo, and resolve longstanding questions regarding relevant pathways and (bio)molecular targets responsible for kinetic (in)stability in vivo. Knowledge gained in this study will contribute to improved BFC designs, which should serve as platforms to expand applications in imaging and therapy of a range of human diseases (e.g., prostate cancer, breast cancer, heart disease).
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).