荒野 泰

An enhancement of the target/nontarget ratio of radioactivity levels enables reliable diagnosis and therapy using polypeptide radiopharmaceuticals in nuclear medicine. In the present study, we investigated the effects of the physicochemical properties of radiometabolites on the radioactivity pharmacokinetics after administration of Tc-99m-labeled polypeptides using 6-hydrazinopyridine-3-carboxylic acid (HYNIC). Four ternary ligands (L) [3-benzoylpyridine (BP), 3-acetylpyridine (AP), 3-nicotinic acid (NIC), pyridine (PY)] with different lipophilicity were selected as coligands for the preparation of Tc-99m-HYNIC-polypeptides. Each of the ternary ligands tested provided Tc-99m-HYNIC-labeled galactosyl-neoalbumin (NGA) and Fab fragments of high stability with high radiochemical purity. Moreover, after administration of each Tc-99m-HYNIC-labeled NGA into normal mice, the respective ternary ligand [Tc-99m](HYNIC-lysine)(tricine)(L) complexes were generated as final radiometabolites in the hepatic lysosome. The partition coefficients of [Tc-99m](HYNIC-lysine)(tricine)(BP), [99mTc](HYNIC-lysine)(tricine)(AP), [99mTc](FrYNIC-lysine)(tricine)(NIC), and [Tc-99m(HYNIC-lysine)(tricine)(PY) were determined to be -2.21, -2.37, -2.93, and -2.73, respectively. Elimination rates of these radiometabolites from the lysosome were enhanced in the order of increasing lipophilicity of the radiometabolites. After injection of the four Tc-99m-HYNIC-labeled Fab fragments into normal mice, blood clearances of radioactivity were similar while radioactivity elimination rates from the kidney were enhanced in the order of increasing lipophilicity of the radiometabolites. The present study indicated that the lipophilicity of the radiometabolites constitutes one important factor affecting their elimination rates from the tissues. Thus, as ternary ligands facilitate alteration of the physicochemical properties of radiometabolites, the use of ternary ligand complexes might be applicable for controlling the pharmacokinetics of Tc-99m-labeled polypeptides.

The present study compares distribution and elimination characteristics of In-111-DTPA-D-Phe(1)-octreotide and In-111-DTPA-L-Phe(1)-octreotide in rats and evaluated the effect of the replacement of the terminal L-phenylalanine by D-phenylalanine on pharmacokinetic profiles of the radiolabelled peptides. Both agents exhibited rapid radioactivity clearance from the blood and most organs and tissues with no systematic and significant differences in activity accumulation. The long-term retention and high radioactivity concentrations for both compounds under study were found in the kidneys and organs with a high density of somatostatin receptors, such as the pancreas and adrenals. The residence times in these organs were longer for In-111-DTPA-D-Phe(1)-octreotide in comparison with In-111-DTPA-L-Phe(1)-octreotide. The major elimination pathway for both radiolabelled peptides was relatively rapid excretion into the urine. Analysis of the renal handling by an employment of the perfused rat kidney showed that both peptides were eliminated mainly by the mechanism of glomerular filtration. Rat liver perfusion experiments confirmed a very low value of bile clearance of radioactivity for both agents under study.