Structure-guided olaparib PET probe enables enhanced PARP-1 precision imaging

Poly (ADP-ribose) polymerase 1 (PARP-1) imaging shows great promise in clinical oncology, offering a non-invasive way to quantify tumor PARP-1 expression, select patients for PARP inhibitor therapy, and monitor treatment response in real-time. However, current PARP-1-targeted radiotracers are highly lipophilic, leading to low tumor uptake, high off-target accumulation, and poor imaging contrast, which restrict their diagnostic utility and accuracy. To overcome these limitations, we developed a series of [¹⁸F]AlF-labeled dimeric positron emission tomography (PET) probes based on the olaparib pharmacophore, leveraging a multivalency strategy with PEGylation. Among the candidates, [¹⁸F]AlF-NOTA-L3 (log P = -2.33 ± 0.50, K_D = 75.2 nM) emerged as the most promising, exhibiting high tumor uptake values of 5.77 ± 0.48, 4.21 ± 0.33, and 3.12 ± 0.19 %ID/g at 10, 30, and 60 min post-injection, respectively, with corresponding tumor-to-muscle ratios of 2.75 ± 0.26, 10.75 ± 2.16, and 10.84 ± 3.24, which were markedly superior to the monomeric probe [¹⁸F]AlF-NOTA-L0. Taken together, [¹⁸F]AlF-NOTA-L3 exhibits reduced lipophilicity, enhanced binding affinity, and superior tumor-to-background contrast, demonstrating significant potential to advance the accuracy for PARP-1 PET imaging for clinical translation.