Discovery of Novel Positron Emission Tomography Tracers for Poly(ADP-Ribose) Polymerase Imaging in Glioblastoma through Photocatalyzed ¹⁸ F-Fluorination

Poly(ADP-ribose) polymerase (PARP)-targeted positron emission tomography (PET) imaging has emerged as a valuable approach for identifying PARP inhibitor (PARPi) nonresponders, monitoring treatment response, and predicting prognosis. However, clinical translation of current tracers, such as [¹⁸F]FTT and [¹⁸F]PARPi, has been hampered by complex radiosynthesis and a high background signal. By leveraging the advantages of the photocatalyzed ¹⁸F-fluorination strategy and analyzing the interaction mode between Olaparib and PARP-1, we developed six novel PARP PET tracers. By finely tuning the physicochemical properties of these tracers with various electron-donating hydroxyl groups, effective direct ¹⁸F-deoxyfluorination, improved tumor uptake, and higher tumor-to-background ratios were achieved. All tracers were efficiently obtained with a high radiochemical purity. An <i>in vitro</i> experiment confirmed sufficient specific PARP binding of [¹⁸F]<b>8a</b>, [¹⁸F]<b>8b</b>, and [¹⁸F]<b>8d</b>, among which [¹⁸F]<b>8a</b> exhibited high tumor uptake (SUV_max = 0.22 ± 0.02) and superior tumor-to-muscle ratio (3.71 ± 0.18) at 1 h postinjection in U87MG tumor-bearing mice on PET/CT images, along with acceptable stability. Collectively, these findings highlight [¹⁸F]<b>8a</b> as a promising PARP PET tracer, combining improved synthetic accessibility with robust imaging performance, and underscore its potential for clinical translation.