A 5‐Azetidinyl BODIPY–Olaparib Conjugate for PARP‐Targeted Nuclear and Orthotopic Oral Tumor Imaging

Poly(ADP-ribose) polymerase (PARP) is a clinically validated therapeutic target and an attractive biomarker for fluorescence-guided tumor imaging. However, the nuclear localization of PARP imposes a stringent requirement on probe design, as fluorophore installation must not compromise nuclear entry of the targeting ligand. Herein, we report a focused series of 5-azetidinyl BODIPY-olaparib conjugates as PARP-targeted fluorescent probes. By attaching olaparib-derived ligands to the 5-position of the BODIPY core through flexible linkers, we sought to preserve conformational flexibility while introducing a donor-acceptor fluorophore with an enlarged Stokes shift. Among the synthesized probes, 1a exhibited the most favorable cellular imaging performance, showing efficient nuclear localization in PARP-overexpressing U87 and Cal27 cells. Competitive blocking with olaparib and comparison with HEK293 cells supported PARP-dependent imaging. In Cal27 xenograft and orthotopic oral tumor models, 1a showed rapid tumor accumulation and clear tumor visualization. It provides a wider range of probe options for intraoperative tracking of oral tumors.