title: Development of (68)Ga-labeled multivalent nitroimidazole derivatives for hypoxia imaging.
abstract: Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed (68)Ga-labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4h in prepared medium at room temperature and in human serum at 37°C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p <0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative ((68)Ga-3: 0.17±0.04, (68)Ga-4: 0.33±0.04, (68)Ga-5: 0.45±0.09, and (68)Ga-6: 0.47±0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p <0.05) at 1h post-injection. The trivalent derivative ((68)Ga-3: 0.10±0.06; (68)Ga-4: 0.20±0.06; (68)Ga-5: 0.33±0.08; (68)Ga-6: 0.59±0.09) also showed the highest standard uptake value for tumor cells at 1h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent (68)Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies.
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Radiation Applied Life Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sudhakara Reddy
authors.initials: SR
authors.lastname: Seelam
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Radiation Applied Life Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Hong
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Banka
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.affiliation: Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Radiation Applied Life Science, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: jmjng@snu.ac.kr.
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000000981:diagnostic imaging*; D003110:Colonic Neoplasms / Q000150:complications / Q000000981:diagnostic imaging*; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D014018:Tissue Distribution
chemical_list: D005710:Gallium Radioisotopes; D009593:Nitroimidazoles
keywords: Bisnitroimidazole; Gallium-68; Hypoxia; Multidentate; Trisnitroimidazole