title: Maleimidoethyl 3-(tri-n-butylstannyl)hippurate: a useful radioiodination reagent for protein radiopharmaceuticals to enhance target selective radioactivity localization.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arano
authors.forename: K
authors.initials: K
authors.lastname: Wakisaka
authors.forename: Y
authors.initials: Y
authors.lastname: Ohmomo
authors.forename: T
authors.initials: T
authors.lastname: Uezono
authors.forename: T
authors.initials: T
authors.lastname: Mukai
authors.forename: H
authors.initials: H
authors.lastname: Motonari
authors.forename: H
authors.initials: H
authors.lastname: Shiono
authors.forename: H
authors.initials: H
authors.lastname: Sakahara
authors.forename: J
authors.initials: J
authors.lastname: Konishi
authors.forename: C
authors.initials: C
authors.lastname: Tanaka
mesh_terms: D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006626:Hippurates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000652:urine; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000652:urine; D007465:Iodohippuric Acid / Q000378:metabolism; D007553:Isotope Labeling; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D014018:Tissue Distribution; D014220:Trialkyltin Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D000418:Albumins; D000911:Antibodies, Monoclonal; D006626:Hippurates; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D014220:Trialkyltin Compounds; C064861:galactosyl-neoglycoalbumin; D007465:Iodohippuric Acid; C088810:maleimidoethyl 3-(tri-n-butylstannyl)hippurate