CHEMICAL DESIGN OF RADIOIODINATED LABELING AGENTS WITH A CLEAVABLE LINKAGE FOR RADIOIMMUNODETECTION AND RADIOIMMUNOTHERAPY OF TUMOR

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Efforts have been made to achieve target-selective radioactivity delivery using monoclonal antibodies. Recent metabolic studies of radiolabeled polypeptides and antibodies indicated that radiometabolites generated after lysosomal proteolysis play a critical role in the radioactivity levels of the tissues. Based on the findings, we conjugated meta-iodohippuric acid to antibodies via a peptide linkage that provides a stable attachment of the radioiodinated compound with antibodies in plasma while facilitating rapid and selective release of the radiolabeled compound in lysosomes. Reduction of hepatic radioactivity levels was achieved without impairing the radioactivity levels in the target. However, this approach may also reduce target radioactivity levels when applied to antibodies that are internalized into target cells.On the other hand, radioiodinated amino acids (IAAs) have been found to be useful as radiopharmaceuticals for tumor imaging due to their longer residence times in tumor … More cells than those in non-target cells. Such characteristics rendered IAAs attractive as radiometabolites liberated from antibodies in lysosomes for targeted imaging and therapy. In this design, the linkage between antibodies and IAAs should be stable enough in plasma to preserve the radioactivity levels in the target delivered by antibodies, whereas rapid and selective release of the designed IAAs from antibodies are required in the lysosomal compartment.In the present study, tumor accumulation and retention of some IAAs were evaluated. Since lower pH environment of the lysosomes is well known, applicability of acid-labile linkages was estimated for lysosome-selective release of the IAAs. The IAAs that possess high in vivo metabolic stability and high urinary excretion characteristics were selected in our previous studies. When incubated with Ehrlich acite tumor cells, radioiodinated α-methyl-L-tyrosine (I-L-AMT) and D-tyrosine (I-D-MIT) showed high accumulation and retention in the tumor cells. Radioiodinated tyrosine derivatives such as I-L-AMT and I-D-MIT were found to be prominent in tumor accumulation.In order to evaluate the pH-dependent cleavage of acid-labile linkages, p-hydroxynorephedrine (PHNE), used as a model compound, was conjugated with maleic anhydride to prepare MNE or citraconic anhydride to prepare CNE, respectively. After purification, radioiodination of MNE and CNE was performed by chloramine T method. Both radioiodinated compounds were incubated at 37℃ in buffered-solutions at various pH. Although both I-MNE and I-CNE remained stable after 48 hr incubation at pH 7.0 and 7.4, selective release of I-PHNE was observed from both conjugates at lower pH values. In addition, I-CNE liberated I-PHNE at a rate much faster than that of I-MNE, presumably due to a presence of bulky side chain in CNE. The findings in this study would provide a good basis for future design of radiolabeled antibodies that liberate radioiodinated amino acids in the lysosomal compartments. Less