title: Development of111In-labeled exendin(9-39) derivatives for single-photon emission computed tomography imaging of insulinoma.
abstract: Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl-diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39),111In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50=2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after111In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of111In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally,111In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: hkimura@mb.kyoto-phu.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Research & Development Division, Arkray, Inc., Yousuien-nai, 59 Gansuin-cho, Kamigyo-ku, Kyoto 602-0008, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Toyoda
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arimitsu
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Hamamatsu
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yagi
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000737:chemistry*; D007340:Insulinoma / Q000000981:diagnostic imaging*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057054:Molecular Imaging; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured
chemical_list: D007205:Indium Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C083773:exendin (9-39)
keywords: (111)In; Exendin(9-39); Glucagon-like peptide 1 receptor; Insulinoma; Single-photon emission computed tomography