Control of radioactivity pharmacokinetics of 99mTc-HYNIC-labeled polypeptides derivatized with ternary ligand complexes.
ABSTRACT
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 99mTc-Iabeled polypeptides using 6-hydrazinopyridine-3carboxylic 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 99mTc-HYNIC-polypeptides. Each of the ternary ligands tested provided 99mTc-HYNIClabeled galactosyl-neoalbumin (NGA) and Fab fragments of high stability with high radiochemical purity. Moreover, after administration of each 99mTc-HYNIC-labeled NGA into normal mice, the respective ternary ligand [99mTc] (HYNIC-lysine)(tricine)(L) complexes were generated as final radiometabolites
in the hepatic lysosome. The partition coefficients of [99mTc](HYNIC-lysine)(tricine)(BP), [99mTc](HYNIC-lysine)(tricine)(AP), [99mTc](HYNIC-lysine)(tricine)(NIC), and [99mTc](HYNIClysine)(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 99mTc-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 ofthe radiometabolites
constitutes one important factor affecting their elimination rates from
the tissues. Thus, as ternary ligands facilitate alteration of the physicochemical
properties ofradiometabolites, the use ofternary ligand complexes might
be applicable for controlling the pharmacokinetics of 99mTc-labeled polypeptides.