Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy

J Med Chem. 2016 Mar 24;59(6):2660-73. doi: 10.1021/acs.jmedchem.5b01881. Epub 2016 Mar 3.


The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / drug effects*
  • Cell Line, Tumor
  • Dinitrophenols / chemical synthesis
  • Dinitrophenols / pharmacology
  • Female
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Nude
  • Prostate-Specific Antigen / immunology*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / therapy*
  • Radioimmunotherapy / methods*
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / pharmacology*
  • Small Molecule Libraries
  • Tissue Distribution
  • Xenograft Model Antitumor Assays


  • Antigens, Neoplasm
  • Dinitrophenols
  • Ligands
  • Radiopharmaceuticals
  • Small Molecule Libraries
  • Prostate-Specific Antigen