Lipophilicity-Optimized PARP-1 Tracers: Minimizing Hepatic Retention for Enhanced Target-to-Background PET Imaging

Developing PARP-1-targeted PET tracers with high tumor-to-background contrast remains challenging. Herein, we report a dual-path optimization strategy to enhance the performance of PARP-1-targeted radiotracers by modulating lipophilicity and incorporating active targeting moieties. A series of ⁶⁸Ga or ¹⁸F-labeled Olaparib derivatives (<b>1a</b>-<b>h</b>) were designed, synthesized, and evaluated. Among these, [^<b>68</b><b>Ga]1c</b>, featuring a DODAGA chelator with enhanced hydrophilicity (Clog <i>p</i> = -2.99 ± 0.07), demonstrated superior tumor uptake (SUV = 0.54 ± 0.02 at 30 min) and sustained retention (SUV = 0.51 ± 0.02 at 4 h), along with significantly improved tumor-to-muscle (T/M = 25.5 at 4 h) and tumor-to-liver (T/L = 7.28 at 4 h) ratios compared to [⁶⁸Ga]DOTA-Olaparib in the 22Rv1 subcutaneous tumor model, and maintained high imaging contrast in the MDA-MB-468 subcutaneous tumor model (tumor-to-muscle ratios all >6.00, tumor-to-liver ratio peaking at 3.16 at 1 h). Competitive blocking studies confirmed PARP-1-specific binding, while biodistribution and cellular assays revealed renal clearance and efficient internalization. In contrast, amino acid-modified derivatives ([^<b>68</b><b>Ga]1d-e</b>, [^<b>18</b><b>F]1g</b>) showed reduced tumor uptake, suggesting limitations in transporter-mediated delivery. PEGylation of [^<b>68</b><b>Ga]1c</b> to yield [^<b>68</b><b>Ga]1h</b> further compromised target affinity, underscoring the sensitivity of PARP-1's binding pocket to steric perturbations. [^<b>68</b><b>Ga]1c</b> demonstrates promise for clinical translation, highlighting the importance of balancing hydrophilicity and molecular size in PARP-1 tracers design.