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

Qianna Wang; Zuojie Li; Yuhao Jiang; Junhong Feng; Qing Ruan; Guangxing Yin; Peiwen Han; Junbo Zhang

doi:10.1016/j.bioorg.2024.108063

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

Bioorg Chem. 2024 Dec 12:154:108063. doi: 10.1016/j.bioorg.2024.108063. Online ahead of print.

Authors

Qianna Wang¹, Zuojie Li¹, Yuhao Jiang², Junhong Feng³, Qing Ruan², Guangxing Yin¹, Peiwen Han¹, Junbo Zhang⁴

Affiliations

¹ Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China.
² Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; Key Laboratory of Beam Technology of the Ministry of Education, School of Physics and Astronomy, Beijing Normal University, Beijing 100875, China.
³ Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; Department of Isotopes, China Institute of Atomic Energy, P.O. Box 2108, Beijing 102413, China.
⁴ Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address: zhjunbo@bnu.edu.cn.

PMID: 39700829
DOI: 10.1016/j.bioorg.2024.108063

Abstract

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 [⁶⁸Ga]Ga-DOTANPB with high radiochemical purity (>95 %). To verify the accuracy of the [⁶⁸Ga]Ga-DOTANPB structure, [^natGa]Ga-DOTANPB was also synthesized, and in vitro affinity experiments were performed, which revealed a high affinity for PARP-1 (IC₅₀ = 82.21 nM). [⁶⁸Ga]Ga-DOTANPB is hydrophilic and has good in vitro stability within 3 h. In in vitro experiments, [⁶⁸Ga]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, [⁶⁸Ga]Ga-DOTANPB showed significant radioconcentration at the tumour site at 0.5 h, 1 h, and 2 h. Biodistribution and autoradiography experiments revealed that [⁶⁸Ga]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 [⁶⁸Ga]Ga-DOTANPB may be a potential niraparib-based PET tracer for targeting PARP-1.

Keywords: DOTA; Gallium-68; Niraparib; PARP; PET.