title: Plasma protein binding of (99m)Tc-labeled hydrazino nicotinamide derivatized polypeptides and peptides.
abstract: 6-Hydrazinopyridine-3-carboxylic acid (HYNIC) constitutes one of the most attractive reagents to prepare (99m)Tc-labeled polypeptides and peptides of various molecular weights in combination with two tricine molecules as coligands. Indeed, (99m)Tc-HYNIC-conjugated IgG showed biodistribution of radioactivity similar to that of (111)In-DTPA-conjugated IgG. However, recent studies indicated significant plasma protein binding when the (99m)Tc labeling procedure was expanded to low molecular weight peptides. In this study, pharmacokinetics of (99m)Tc-HYNIC-conjugated IgG, Fab and RC160 using tricine were compared with their radioiodinated counterparts to evaluate this (99m)Tc-labeling method. In mice, [(99m)Tc](HYNIC-IgG)(tricine)(2) and [(99m)Tc](HYNIC-Fab)(tricine)(2) showed persistent localization of radioactivity in tissues when compared with their (125)I-labeled counterparts. [(99m)Tc](HYNIC-IgG)(tricine)(2) eliminated from the blood at a rate similar to that of (125)I-labeled IgG, while [(99m)Tc](HYNIC-Fab)(tricine)(2) showed significantly slower clearance of the radioactivity than (125)I-labeled Fab. On size-exclusion HPLC analyses, little changes were observed in radiochromatograms after incubation of [(99m)Tc](HYNIC-IgG)(tricine)(2) in murine plasma. However, [(99m)Tc](HYNIC-Fab)(tricine)(2) and [(99m)Tc](HYNIC-RC160)(tricine)(2) demonstrated significant increases in the radioactivity in higher molecular weight fractions in plasma. Formation of higher molecular weight species was reduced when [(99m)Tc](HYNIC-RC160)(tricine)(2) was stabilized with nicotinic acid (NIC) to generate [(99m)Tc](HYNIC-RC160)(tricine)(NIC). [(99m)Tc](HYNIC-RC160)(tricine)(NIC) also demonstrated significantly faster clearance of the radioactivity from the blood than [(99m)Tc](HYNIC-RC160)(tricine)(2). These findings suggested that one of the tricine coligands in (99m)Tc-HYNIC-labeled (poly)peptides would be replaced with plasma proteins to generate higher molecular weight species that exhibit slow blood clearance. In addition, the molecular sizes of parental peptides played an important role in the progression of the exchange reaction of one of the tricine coligands with plasma proteins.
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: M
authors: M
authors: Ono
authors: Y
authors: Y
authors: Arano
authors: T
authors: T
authors: Mukai
authors: T
authors: T
authors: Uehara
authors: Y
authors: Y
authors: Fujioka
authors: K
authors: K
authors: Ogawa
authors: S
authors: S
authors: Namba
authors: M
authors: M
authors: Nakayama
authors: T
authors: T
authors: Saga
authors: J
authors: J
authors: Konishi
authors: K
authors: K
authors: Horiuchi
authors: A
authors: A
authors: Yokoyama
authors: H
authors: H
authors: Saji
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G / Q000097:blood; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015609:Organotechnetium Compounds / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004369:Pentetic Acid / Q000493:pharmacokinetics; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C099153:technetium Tc 99m hydrazinonicotinate-IgG; D004369:Pentetic Acid