Synthesis and bioevaluation of a new 68Ga-labelled niraparib derivative that targets PARP-1 for tumour imaging

Poly ADP-ribose polymerase (PARP) inhibitors prevent the repair of DNA single-strand breaks in cancer cells with abnormal homologous recombination, producing a synthetic lethal effect. Thus, PARP inhibitors have become clinically effective anticancer drugs. Labelling with radionuclides may extend the use of PARP inhibitors as tracers in nuclear medicine diagnostics, helping to stratify patients. In the present study, niraparib was selected as a skeleton molecule modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labelled with gallium-68 to obtain [Ga-68]Ga-DOTANPB with high radiochemical purity (>95 %). To verify the accuracy of the [Ga-68]Ga-DOTANPB structure, [Ga-nat]Ga-DOTANPB was also synthesized, and in vitro affinity experiments were performed, which revealed a high affinity for PARP-1 (IC50 = 82.21 nM). [Ga-68]Ga-DOTANPB is hydrophilic and has good in vitro stability within 3 h. In in vitro experiments, [Ga-68]Ga-DOTANPB has a high uptake in HeLa cells and can enter the cell to target PARP-1. In coronal PET imaging of HeLa tumour-bearing mice, [Ga-68]Ga-DOTANPB showed significant radioconcentration at the tumour site at 0.5 h, 1 h, and 2 h. Biodistribution and autoradiography experiments revealed that [Ga-68]Ga-DOTANPB has obvious tumour uptake and can be significantly inhibited (3.37 +/- 0.33 % ID/g vs. 2.50 +/- 0.27 % ID/g, **P < 0.01), suggesting that it has PARP-1 specificity. Thus, these findings suggested that [Ga-68]Ga-DOTANPB may be a potential niraparib-based PET tracer for targeting PARP-1.