PARP inhibitors are proven chemotherapeutics and serve as lead structures for the development of PARP-targeted in vivo imaging probes. Given the clinical potential of PARP imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacologi-cal profiles over established PARP imaging agents is warranted. Here, we present a novel 18F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [18F]talazoparib (RCY: 13 ± 3.4 %; n = 4; molar radioactivity 52 – 176 GBq/μmol) was achieved using a “Design of Experiments” (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8S, 9R)-[18F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xeno-graft-bearing mice (10.2 ± 1.5). Despite expected uptake into muscle, bone, and abdominal tissue, a favorable pharmacological profile in terms of excretion, blood half-life, and target engagement was observed in the pilot in vivo study. This synthesis of [18F]talazoparib exemplifies how a DoE based tracer development pipeline can enable the radiosyntheses of clinically relevant but synthetically challenging radiolabeled compounds of high interest to the imaging community.