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^99mTc Labeling of Proteins: Initial Evaluation of a Novel Diaminedithiol Bifunctional Chelating Agent¹

Department of Environmental Health Sciences, Division of Radiation Health Sciences, The Johns Hopkins University, Baltimore, Maryland 21205

The initial evaluation of a novel thiolactone bifunctional chelating agent, 1, for facile introduction of the diaminedithiol (DADT) ligand system onto proteins for subsequent labeling with ^99mTc under mild conditions is presented. For human serum albumin and a monoclonal anti-colon carcinoma antibody (B72.3), time-dependent coupling was achieved at pH 7–9 at room temperature. The coupled proteins could be labeled in a direct fashion (Sn²⁺/^99mTcO₄^-) and by exchange labeling (with preformed ^99mTc-glucoheptonate) in good to excellent yields at pH 7. In contrast, the unmodified proteins could be labeled only by direct methods with maximum yields of 30%. The labeled, coupled proteins were purified by high performance liquid chromatography and found to be stable in vitro over a 20-h period of study with no evidence for the loss of label. This exceptional stability is due to the chelation of ^99mTc by the DADT ligand since 66% (3.5 h) and 47% (20 h) of the label were lost from directly labeled unmodified human serum albumin and the unmodified antibody, respectively. Biodistribution studies in normal mice and rabbits confirmed the stability of the ^99mTc-DADT-labeled proteins compared to the ^99mTc-labeled unmodified proteins in vivo. Thus, the novel thiolactone 1 is a useful bifunctional chelating agent for introducing the DADT ligand system onto a variety of proteins for subsequent incorporation of technetium under mild conditions such that the resultant labeled products are stable in vitro and in vivo.