Maleimidoethyl 3-(tri-n-butylstannyl)hippurate: a useful radioiodination reagent for protein radiopharmaceuticals to enhance target selective radioactivity localization

J Med Chem. 1994 Aug 5;37(16):2609-18. doi: 10.1021/jm00042a014.


In pursuit of radiolabeled monoclonal antibodies (mAbs) with rapid urinary excretion of radioactivity from nontarget tissues, radioiodinated mAbs releasing a m-iodohippuric acid from the mAbs in nontarget tissues were designed. A novel reagent, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was synthesized by reacting N-(hydroxyethyl)maleimide with N-Boc-glycine before coupling with N-succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE). MIH possessed a maleimide group for mAb conjugation and a butylstannyl moiety for high-yield and site-specific radioiodination, and the two functional groups were linked via an ester bond to release m-iodohippuric acid. To investigate the fate of radiolabels after lysosomal proteolysis, hepatic parenchymal cells were used as a model nontarget tissue and 131I-labeled MIH was conjugated with galactosyl-neoglycoalbumin (NGA). Further conjugation of [131I]MIH with a mAb against osteogenic sarcoma (OST7) after reduction of its disulfide bonds was followed up. In murine biodistribution studies, [131I]MIH-NGA exhibited rapid accumulation in the liver followed by radioactivity elimination from the liver at a rate that was identical to and faster than those of 131I-labeled NGA via direct iodination ([131I]NGA) and [131I]ATE-labeled NGA, respectively. While [131I]NGA indicated high radioactivity levels in the murine neck, stomach, and blood, such increases in the radioactivity count were not detectable by the administration of either [131I]MIH-NGA or [131I]ATE-NGA. At 6 h postinjection of [131I]MIH-NGA, 80% of the injected radioactivity was recovered in the urine. Analyses of urine samples indicated that m-iodohippuric acid was the sole radiolabeled metabolite. In biodistribution studies using [131I]-MIH-OST7 and [131I]ATE-OST7, while both 131I-labeled OST7s registered almost identical radioactivity levels in the blood up to 6 h postinjection, the former demonstrated a lower radioactivity level than [131I]ATE-OST7 in nontarget tissues throughout the experiment. Such chemical and biological characteristics of MIH would enable high target/nontarget ratios in diagnostic and therapeutic nuclear medicine using mAbs and other polypeptides.

MeSH terms

  • Albumins / pharmacokinetics
  • Animals
  • Antibodies, Monoclonal* / therapeutic use
  • Chromatography, High Pressure Liquid
  • Drug Stability
  • Hippurates / chemical synthesis*
  • Hippurates / pharmacokinetics
  • Hippurates / urine
  • Indicators and Reagents
  • Iodine Radioisotopes* / pharmacokinetics
  • Iodine Radioisotopes* / urine
  • Iodohippuric Acid / metabolism
  • Isotope Labeling
  • Kinetics
  • Liver / metabolism
  • Lysosomes / metabolism
  • Mice
  • Tissue Distribution
  • Trialkyltin Compounds / chemical synthesis*
  • Trialkyltin Compounds / pharmacokinetics
  • Trialkyltin Compounds / urine


  • Albumins
  • Antibodies, Monoclonal
  • Hippurates
  • Indicators and Reagents
  • Iodine Radioisotopes
  • Trialkyltin Compounds
  • galactosyl-neoglycoalbumin
  • Iodohippuric Acid
  • maleimidoethyl 3-(tri-n-butylstannyl)hippurate