Enhanced tumor retention of a radiohalogen label for site-specific modification of antibodies

J Med Chem. 2013 Dec 12;56(23):9418-26. doi: 10.1021/jm401365h. Epub 2013 Nov 5.


A known limitation of iodine radionuclides for labeling and biological tracking of receptor targeted proteins is the tendency of iodotyrosine to rapidly diffuse from cells following endocytosis and lysosomal degradation. In contrast, radiometal-chelate complexes such as indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (In-111-DOTA) accumulate within target cells due to the residualizing properties of the polar, charged metal-chelate-amino acid adduct. Iodine radionuclides boast a diversity of nuclear properties and chemical means for incorporation, prompting efforts to covalently link radioiodine with residualizing molecules. Herein, we describe the Ugi-assisted synthesis of [I-125]HIP-DOTA, a 4-hydroxy-3-iodophenyl (HIP) derivative of DOTA, and demonstration of its residualizing properties in a murine xenograft model. Overall, this study displays the power of multicomponent synthesis to yield a versatile radioactive probe for antibodies across multiple therapeutic areas with potential applications in both preclinical biodistribution studies and clinical radioimmunotherapies.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / chemistry
  • Antibodies, Monoclonal, Murine-Derived / metabolism*
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Coordination Complexes / metabolism
  • Dipeptides / chemical synthesis*
  • Dipeptides / metabolism
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / metabolism
  • Immunoconjugates / chemistry*
  • Immunoconjugates / metabolism
  • Indium Radioisotopes
  • Mice
  • Radioimmunotherapy
  • Succinimides / chemical synthesis*
  • Succinimides / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Murine-Derived
  • Coordination Complexes
  • Dipeptides
  • Heterocyclic Compounds, 1-Ring
  • Immunoconjugates
  • Indium Radioisotopes
  • Succinimides
  • indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid