Design, Synthesis, and Preclinical Evaluation of [18F]FPON, a First-In-Class PET Tracer Targeting Proliferating Cell Nuclear Antigen for Glioblastoma Imaging

Proliferating cell nuclear antigen (PCNA) is a central regulator of glioma stem cell maintenance and therapy resistance, yet no noninvasive method exists to visualize its expression in vivo. We developed [18F]FPON, a first-in-class small-molecule PET tracer targeting PCNA, derived from the clinical inhibitor AOH1996. FPON binds recombinant PCNA with a Kd of 900.8 ± 131.2 nM, comparable to AOH1996. [18F]FPON is synthesized in one step with a decay-corrected radiochemical yield of 11.43 ± 4.03% (n = 6) and >95% radiochemical purity, readily crosses the blood−brain barrier, and remains >87% intact in brain at 60 min post-injection. In orthotopic U87 glioma xenografts, [18F]FPON exhibits specific tumor uptake (SUVr = 2.58 ± 0.38 vs contralateral brain), which is significantly reduced by AOH1996 (SUVr = 1.62 ± 0.24, p < 0.01). These results establish [18F]FPON as a promising PET tracer for noninvasive imaging of PCNA and support its potential use as a companion diagnostic for PCNA-targeted therapies.