| Abstract
| - Radiochemical design of polypeptides using metabolizable linkageswould be attractive toenhance target-selective localization of radioactivity for diagnosticand therapeutic nuclearmedicine. However, while use of ester bonds as the linkage allowsselective release of thedesigned radiometabolite from covalently conjugated polypeptides afterlysosomal proteolysisin nontarget tissues, low plasma stability of ester bonds causes adecrease in radioactivitylevels of the target. In pursuit of new metabolizable linkagesthat provide stable attachmentof radiolabels with polypeptide in plasma while facilitating rapid andselective release ofdesigned radiometabolites of rapid urinary excretion in lysosomes, anew radioiodination reagentwith l-lysine as the metabolizable linkage to liberatem-iodohippuric acid (l-HML) wasdesignedand synthesized. Stabilities of the metabolizable linkage in serumand cleavabilities of thelinkage in lysosomal proteolysis in hepatic cells were investigatedafter conjugation of [131I]-l-HML with galactosyl-neoglycoalbumin (NGA). Forcomparison, a radioiodination reagentwith an ester bond to release m-iodohippuric acid (MIH) wasconjugated with NGA under similarconditions. When incubated in human serum,[131I]-l-HML-NGA liberated less than 3% oftheinitial radioactivity after 24 h, whereas[125I]MIH-NGA released more than 60% ofitsradioactivity during the same interval. In biodistributionstudies, [131I]-l-HML-NGA demonstrated radioactivity elimination from murine liver at a rate andexcretion route similar to[125I]MIH-NGA. Analyses of murine urine afterinjection of [131I]-l-HML-NGA indicated asingleradioactivity peak at fractions identical to those ofm-iodohippuric acid. Biodistributionstudiesof radioiodinated NGAs with d-lysine or cadaverine as thelinkages demonstrated a delayedelimination rate from murine liver with significantly higherradioactivity being excreted inthe feces at 24 h postinjection. Thus, l-HML is thefirst reagent that allows stable attachmentof radiolabel with polypeptide in serum while facilitating selectiverelease of a radiometabolitewith rapid urinary excretion from covalently conjugated polypeptidesafter lysosomal proteolysisat a rate similar to that of ester bonds. Thus, l-HMLis potentially useful for the radioiodinationof polypeptides for diagnostic and therapeutic purposes.
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