Design, synthesis and biological evaluation of negatively charged ¹¹¹In-DTPA-octreotide derivatives.
Our previous studies indicated that (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA)-octreotide derivatives with an additional negative charge by replacing N-terminal d-phenylalanine (d-Phe) with an acidic amino acid such as l-aspartic acid (Asp) or its derivative exhibited low renal radioactivity levels when compared with (111)In-DTPA-D-Phe(1)-octreotide. On the basis of the findings, we designed, synthesized and evaluated two Asp-modified (111)In-DTPA-conjugated octreotide derivatives, (111)In-DTPA-Asp(1)-octreotide and (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide. While (111)In-DTPA-Asp(1)-octreotide showed negligible AR42J cell uptake, (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited AR42J cell uptake similar to that of (111)In-DTPA-D-Phe(1)-octreotide. When administered to AR42J tumor-bearing mice, (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited renal radioactivity levels significantly lower than did (111)In-DTPA-D-Phe(1)-octreotide at 1 and 3 h post-injection. No significant differences were observed in tumor accumulation between (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide and (111)In-DTPA-D-Phe(1)-octreotide after 1 and 3h injection. The findings in this study suggested that an interposition of an Asp at an appropriate position in (111)In-DTPA-D-Phe(1)-octreotide would constitute a useful strategy to develop (111)In-DTPA-D-Phe(1)-octreotide derivatives of low renal radioactivity levels while preserving tumor accumulation.
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
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
K
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
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D006207:Half-Life; D051379:Mice; D008819:Mice, Nude; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004369:Pentetic Acid / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D019275:Radiopharmaceuticals; C094279:indium-111-octreotide; D004369:Pentetic Acid; D015282:Octreotide
(111)In-DTPA-d-Phe(1)-octreotide; Aspartic acid; Negative charge; Renal radioactivity