title: (99m)Tc-HYNIC-derivatized ternary ligand complexes for (99m)Tc-labeled polypeptides with low in vivo protein binding.
abstract: 6-Hydrazinopyridine-3-carboxylic acid (HYNIC) is a representative agent used to prepare technetium-99m ((99m)Tc)-labeled polypeptides with tricine as a coligand. However, (99m)Tc-HYNIC-labeled polypeptides show delayed elimination rates of the radioactivity not only from the blood but also from nontarget tissues such as the liver and kidney. In this study, a preformed chelate of tetrafluorophenol (TFP) active ester of [(99m)Tc](HYNIC)(tricine)(benzoylpyridine: BP) ternary complex was synthesized to prepare (99m)Tc-labeled polypeptides with higher stability against exchange reactions with proteins in plasma and lysosomes using the Fab fragment of a monoclonal antibody and galactosyl-neoglycoalbumin (NGA) as model polypeptides. When incubated in plasma, [(99m)Tc](HYNIC-Fab)(tricine)(BP) showed significant reduction of the radioactivity in high molecular weight fractions compared with [(99m)Tc](HYNIC-Fab)(tricine)(2.) When injected into mice, [(99m)Tc](HYNIC-NGA)(tricine)(BP) was metabolized to [(99m)Tc](HYNIC-lysine)(tricine)(BP) in the liver with no radioactivity detected in protein-bound fractions in contrast to the observations with [(99m)Tc](HYNIC-NGA)(tricine)(2.) In addition, [(99m)Tc](HYNIC-NGA)(tricine)(BP) showed significantly faster elimination rates of the radioactivity from the liver as compared with [(99m)Tc](HYNIC-NGA)(tricine)(2.) Similar results were observed with (99m)Tc-labeled Fab fragments where [(99m)Tc](HYNIC-Fab)(tricine)(BP) exhibited significantly faster elimination rates of the radioactivity not only from the blood but also from the kidney. These findings indicated that conjugation of [(99m)Tc](HYNIC)(tricine)(BP) ternary ligand complex to polypeptides accelerated elimination rates of the radioactivity from the blood and nontarget tissues due to low binding of the [(99m)Tc](HYNIC)(tricine)(BP) complex with proteins in the blood and in the lysosomes. Such characteristics would render the TFP active ester of [(99m)Tc](HYNIC)(tricine)(BP) complex attractive as a radiolabeling reagent for targeted imaging.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, 606-8501, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ono
authors.forename: Y
authors.initials: Y
authors.lastname: Arano
authors.forename: T
authors.initials: T
authors.lastname: Mukai
authors.forename: Y
authors.initials: Y
authors.lastname: Fujioka
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: T
authors.initials: T
authors.lastname: Uehara
authors.forename: T
authors.initials: T
authors.lastname: Saga
authors.forename: J
authors.initials: J
authors.lastname: Konishi
authors.forename: H
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D005419:Flavonoids; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010936:Plant Extracts; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C400057:99mTc(HYNICtide)(tricine)(TPPTS); D005419:Flavonoids; C112288:LI 1370; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D010936:Plant Extracts; D019275:Radiopharmaceuticals