DDDR-75. LDLR-Mediated Tumor Targeting Using a203Pb-Labeled Peptide: A Novel Strategy for Glioblastoma Imaging

Abstract INTRODUCTION Building on the established correlation between low-density-lipoprotein- receptor (LDLR) overexpression and glioblastoma (GBM) progression, we synthesized a targeted library of 203Pb-labeled conjugates (RMX-VH series). This abstract highlights the development of the lead compound, 203Pb-DOTAM-RMX-VH-PKM, as a novel molecular imaging agent of glioblastoma METHODS Radiochemical and chemical purity were assessed using iTLC and HPLC. 203Pb was sourced from the University of Alabama, Birmingham (UAB) Cyclotron Facility. SPECT imaging studies were conducted in both subcutaneous U87MG xenograft and intracranial U251 orthotopic glioblastoma models at multiple time points using the Gamma-Eye SPECT-camera (BIOEMTECH, Greece). Following imaging, animals were euthanized, and major organs and tumors were harvested, weighed, and analyzed for radioactivity using a Wizard2 Gamma Counter (PerkinElmer, Waltham, MA). %ID/g was calculated and decay-corrected to the time-of-injection. RESULTS The radiolabeling of 203Pb-RMX-VH-PKM proceeded with high efficiency, maintaining structural and radiochemical stability for at least 48 hours. The PKM motif extended its systemic plasma half-life to 9.2 hours, substantially longer than the 1.3-hour half-life of the RMX-VH. Biodistribution studies in GBM-xenograft models demonstrated favorable tumor-targeting properties. Tumor retention at 1 hour reached 6.2±1.8%ID/g, remained steady through 3-hours, and declined to 3.3±0.2%ID/g by 24-hours, indicating sustained tumor association. Hepatic accumulation remained relatively constant between 2-24 hours, consistent with the high expression of LDLR. The bone marrow uptake was low at early time points (1.2±0.7%ID/g at 1-hour) and decreased by a factor of three at 24 hours, suggesting a strong coordination of 203Pb and minimal transchelation. Uptake in other non-target organs followed a similar declining trend. SPECT imaging of 203Pb-RMX-VH-PKM in orthotopic U251-glioblastoma models confirmed rapid and efficient tumor localization, with intratumoral signal evident as early as 1hour-post-injection. PET/CT imaging using 18F-fluciclovine (Axumin) enabled the colocalization of tumors based on the radiotracer’s specific uptake. CONCLUSION These results highlight the potential of 203Pb-RMX-VH-PKM as a next-generation radiopharmaceutical for LDLR-targeted imaging of aggressive glioblastoma, offering improved tumor retention and longer circulation time.