Click Covalent-Targeted Radionuclide Therapy for Prostate Cancer

  • J Med Chem. 2025 Aug 28;68(16):17794-17807. doi: 10.1021/acs.jmedchem.5c01515.
Weipeng Yong  1 ,  Shu Zhang  2 ,  Zhoudong Zhang  3 ,  Zhihao Li  1 ,  Yu Qin  1 ,  Xunhao Qi  1 ,  Dong Wang  1 ,  Yujuan Zhang  4 ,  Jianguo Li  2 ,  Zhiyong Liu  1 ,  Ran Zhu  1 ,  Huanqiu Li  3 ,  Guanglin Wang  1
Affiliations
  • 1. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
  • 2. Division of Radiation Medicine and Environmental Medicine, CAEA Center of Excellence on Nuclear Technology Applications for Nonclinical Evaluation for Radiopharmaceutical, CNNC Key Laboratory on Radio-Toxicology and Radiopharmaceutical Preclinical Evaluation, Shanxi Key Laboratory of Drug Toxicology and Preclinical Studies for Radiopharmaceutical, China Institute for Radiation Protection, Taiyuan 030006, China.
  • 3. Jiang Su Key Laboratory of Antibody-Targeted Drug Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 4. Experimental Center of Soochow University, Department of Medicine, Soochow University, Suzhou 215123, PR China.
PMID: 40787824 DOI: 10.1021/acs.jmedchem.5c01515
Abstract

Targeted radionuclide therapy represents a promising therapeutic method for treating Cancer. However, currently approved radioligands still require improvement in terms of tumor uptake and retention. This study employed molecular simulation to design a novel radioligand, designated PSMA-MAL-5, which covalently binds to the prostate-specific membrane antigen (PSMA). This ligand can be efficiently radiolabeled with the beta emitter (177Lu) and the alpha emitter (225Ac) and exhibits a high level of radiostability. Autoradiography confirmed that 177Lu-PSMA-MAL-5 binds covalently to PSMA. In vivo experiments demonstrated that the radioligand can effectively target PSMA-positive tumors, with an area under the curve of tumor uptake higher than that observed for 177Lu-PSMA-617 (2517 ± 499 h %ID/cm3 vs 575 ± 75 h %ID/cm3). Tumor inhibition studies indicated that the radioligand exhibited a notable tumor inhibitory effect on tumor growth, showing promise as a tool for targeted radionuclide therapy of PSMA-positive prostate Cancer.

Products