A novel bifunctional chelating agent based on bis(hydroxamamide) for 99mTc labeling of polypeptides

This paper describes the synthesis and biological evaluation of a novel bifunctional chelating agent (BCA) based on bis(hydroxamamide) for 99mTc labeling of polypeptides. We successfully designed and synthesized C3(BHam)2―COOH as a new BCA. C3(BHam)2―COOH formed a stable 99mTc complex and enabled us to prepare 99mTc-labeled polypeptides by using a 2,3,5,6-tetrafluorophenol (TFP) active ester of C3(BHam)2―COOH. 99mTc-C3(BHam)2―HSA prepared with C3(BHam)2―TFP was stable in both murine plasma and an excess of l-cysteine without any dissociation of 99mTc from polypeptides. Furthermore, the blood clearance of 99mTc-C3(BHam)2―HSA in mice was similar to that of 125I-HSA, suggesting that C3(BHam)2―COOH retained stable binding between 99mTc and the polypeptides in vivo. When 99mTc-C3(BHam)2―NGA was injected into mice, the radioactivity showed high hepatic uptake early on and a rapid clearance from the liver, indicating that C3(BHam)2―COOH did not affect the pharmacokinetics of polypeptides in vivo and gave radiometabolites, which displayed a rapid elimination from the liver. Such characteristics would render C3(BHam)2―COOH attractive as a new BCA for 99mTc labeling of polypeptides.