Redesign of negatively charged111In-DTPA-octreotide derivative to reduce renal radioactivity.
BACKGROUND
Radiolabeled octreotide derivatives have been studied as diagnostic and therapeutic agents for somatostatin receptor-positive tumors. To prevent unnecessary radiation exposure during their clinical application, the present study aimed to develop radiolabeled peptides which could reduce radioactivity levels in the kidney at both early and late post-injection time points by introducing a negative charge with an acidic amino acid such as L-aspartic acid (Asp) at a suitable position in111In-DTPA-conjugated octreotide derivatives.


METHODS
Biodistribution of the radioactivity was evaluated in normal mice after administration of a novel radiolabeled peptide by a counting method. The radiolabeled species remaining in the kidney were identified by comparing their HPLC data with those obtained by alternative synthesis.


RESULTS
The designed and synthesized radiolabeled peptide111In-DTPA-d-Phe-1-Asp0-d-Phe1-octreotide exhibited significantly lower renal radioactivity levels than those of the known111In-DTPA-d-Phe1-octreotide at 3 and 24h post-injection. The radiolabeled species in the kidney at 24h after the injection of new octreotide derivative represented111In-DTPA-d-Phe-OH and111In-DTPA-d-Phe-Asp-OH as the metabolites. Their radiometabolites and intact111In-DTPA-conjugated octreotide derivative were observed in urine within 24h post-injection.


CONCLUSIONS
The present study provided a new example of an111In-DTPA-conjugated octreotide derivative having the characteristics of both reduced renal uptake and shortened residence time of radioactivity in the kidney. It is considered that this kinetic control was achieved by introducing a negative charge on the octreotide derivative thereby suppressing the reabsorption in the renal tubules and affording the radiometabolites with appropriate lipophilicity.
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Nobuhiro
N
Oshima
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan; Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan.
Hiromichi
H
Akizawa
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Hidekazu
H
Kawashima
Graduate School of Medicine, Hokkaido University, Kita 15 nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Songji
S
Zhao
Graduate School of Medicine, Hokkaido University, Kita 15 nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Yan
Y
Zhao
Graduate School of Medicine, Hokkaido University, Kita 15 nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Ken-Ichi
KI
Nishijima
Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Takaramachi, Kanazawa, Ishikawa, 920-8640, Japan.
Yoji
Y
Kitamura
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Yasushi
Y
Arano
Graduate School of Medicine, Hokkaido University, Kita 15 nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan; Central Institute of Isotope Sciences, Hokkaido University, Kita 15 nishi 7, Kita-ku, Sapporo, Hokkaido, 060-0815, Japan.
Yuji
Y
Kuge
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan. Electronic address: ohkura@hoku-iryo-u.ac.jp.
Kazue
K
Ohkura
D000818:Animals; D015195:Drug Design; D004355:Drug Stability; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D015282:Octreotide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D011851:Radioactivity; D014018:Tissue Distribution
C497824:111In-octreotide, DTPA(0)-; D004369:Pentetic Acid; D015282:Octreotide
(111)In-DTPA-peptide; Negative charge; Octreotide; Radiometabolite; Renal radioactivity