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 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.
Arano
Y
Y
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Wakisaka
K
K
Ohmomo
Y
Y
Uezono
T
T
Mukai
T
T
Motonari
H
H
Shiono
H
H
Sakahara
H
H
Konishi
J
J
Tanaka
C
C
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
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