title: Synthesis and characterization of nitroimidazole derivatives for 68Ga-labeling and testing in tumor xenografted mice.
abstract: Radiolabeled nitroimidazole (NI) derivatives have been used for imaging hypoxic tissues. We synthesized NI derivatives conjugated with bifunctional chelating agents such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and isothiocyanatobenzyl-NOTA (SCN-NOTA) via ethyleneamine bridge by formation of amide and thiourea bond, respectively. We proved that amide oxygen of Ga-NOTA-NI contributes to the formation of metal complex by X-ray crystallography. We labeled them with (68)Ga and found that both (68)Ga-NOTA-NI and (68)Ga- SCN-NOTA-NI were labeled in high efficiency (>96%) and were stable at room temperature in the prepared medium and at 37 degrees C in human serum. In vitro cell uptake experiments using CHO and CT-26 cell lines showed significantly increased uptakes of both of the agents in hypoxic condition. Biodistribution study in CT-26 xenografted mice showed increasing tumor to muscle ratios. (68)Ga-NOTA-NI showed lower intestine uptake than (68)Ga-NOTA-SCN-NI due to hydrophilicity. Also, (68)Ga-NOTA-NI showed higher tumor uptake than (68)Ga-NOTA-SCN-NI in an animal PET study. In conclusion, we successfully developed (68)Ga labeled NI derivatives for hypoxic tissue imaging.
authors.affiliation: Department of Nuclear Medicine, Radiation Applied Life Sciences, Institute of Radiation Medicine, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Lathika
authors.initials: L
authors.lastname: Hoigebazar
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Choi
authors.forename: Dinesh
authors.initials: D
authors.lastname: Shetty
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.forename: Myung Chul
authors.initials: MC
authors.lastname: Lee
authors.forename: Young Keun
authors.initials: YK
authors.lastname: Chung
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D016466:CHO Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005709:Gallium Isotopes; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D001798:Blood Proteins; D056831:Coordination Complexes; D005709:Gallium Isotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals