MALEIMIDOETHYL 3-(TRI-N-BUTYLSTANNYL)HIPPURATE - A USEFUL RADIOIODINATION REAGENT FOR PROTEIN RADIOPHARMACEUTICALS TO ENHANCE TARGET SELECTIVE RADIOACTIVITY LOCALIZATION

In pursuit of radiolabeled monoclonal antibodies (mAbs) with rapid uri nary excretion of radioactivity from nontarget tissues, radioiodinated mAbs releasing a m-iodohippuric acid from the mAbs in nontarget tissu es were designed. A novel reagent, maleimidoethyl 3-(tri-n-butylstanny l)hippurate (MIH), was synthesized by reacting N-(hydroxyethyl)maleimi de with N-Boc-glycine before coupling with N-succinimidyl 3-(tri-n-but ylstannyl)benzoate (ATE). MIH possessed a maleimide group for mAb conj ugation and a butylstannyl moiety for high-yield and site-specific rad ioiodination, and the two functional groups were linked via an ester b ond to release m-iodohippuric acid. To investigate the fate of radiola bels after lysosomal proteolysis, hepatic parenchymal cells were used as a model nontarget tissue and I-131-labeled MIH was conjugated with galactosyl-neoglycoalbumin (NGA). Further conjugation of[I-131]MIH wit h a mAb against osteogenic sarcoma (OST7) after reduction of its disul fide bonds was followed up. In murine biodistribution studies, [I-131] MIH-NGA exhibited rapid accumulation in the liver followed by radioact ivity elimination from the liver at a rate that was identical to and f aster than those of I-131-labeled NGA via direct iodination ([I-131]NG A) and [I-131]ATE-labeled NGA, respectively. While [I-131]NGA indicate d high radioactivity levels in the murine neck, stomach, and blood, su ch increases in the radioactivity count were not detectable by the adm inistration of either [I-131]MIH-NGA or [I-131]ATE-NGA. At 6 h postinj ection of [I-131]MIH-NGA, 80% of the injected radioactivity was recove red in the urine. Analyses of urine samples indicated that m-iodohippu ric acid was the sole radiolabeled metabolite. In biodistribution stud ies using [I-131]MIH-OST7 and [I-131]ATE-OST7, while both I-131-labele d OST7s registered almost identical radioactivity levels in the blood up to 6 h postinjection, the former demonstrated a lower radioactivity level than [I-131]ATE-OST7 in nontarget tissues throughout the experi ment. Such chemical and biological characteristics of MIH would enable high target/nontarget ratios in diagnostic and therapeutic nuclear me dicine using mAbs and other polypeptides.