Synthesis and Preliminary Biological Evaluation of a Structurally Modified Niraparib-Based PARP-Targeted PET Tracer...

Poly-(ADP-ribose) polymerase (PARP) is highly expressed in various malignancies and represents an important therapeutic target. Noninvasive evaluation of PARP expression is therefore of potential clinical significance for patient stratification. In this study, we developed and evaluated [⁶⁸Ga]-Ga-DOTA-MK-4827, a structurally modified PARP-targeted radiotracer derived from niraparib, featuring a two-carbon linker between the DOTA chelator and the pharmacophore. [⁶⁸Ga]-Ga-DOTA-MK-4827 demonstrated high uptake in MDA-MB-231 and OE-19 tumors with elevated PARP-1 expression, which was significantly reduced by blocking, supporting a PARP-related component of tumor accumulation. The tracer exhibited favorable pharmacokinetics, including high hydrophilicity and predominantly renal clearance, resulting in low abdominal background activity. Positron emission tomography (PET) imaging enabled clear tumor visualization with good contrast, supported by biodistribution findings. Preliminary clinical imaging further showed notable uptake in an esophageal cancer lesion, with immunohistochemical confirmation of PARP-1 expression in the biopsied tissue. These results suggest that [⁶⁸Ga]-Ga-DOTA-MK-4827 has potential as a PARP-targeted PET tracer for tumor imaging and merits further investigation in larger clinical cohorts.