title: Modulation of in vivo distribution through chelator: Synthesis and evaluation of a 2-nitroimidazole-dipicolylamine-(99m)Tc(CO)3 complex for detecting tumor hypoxia.
abstract: Previous studies have clearly demonstrated strong correlation between in vivo distribution and blood clearance of radiopharmaceuticals for the detection of hypoxia. Present study describes an attempt to improve the in vivo distribution of a previously reported 2-nitroimidazole-(99m)Tc(CO)3 complex by tuning its blood clearance pattern through structural modification of the ligand. Herein, a 2-nitroimidazole-dipicolylamine ligand (2-nitroimidazole-DPA) was synthesized in a two-step procedure and radiolabeled with (99m)Tc(CO)3 core. Subsequently, the complex was evaluated in Swiss mice bearing fibrosarcoma tumor. As intended by its design, 2-nitroimidazole-DPA-(99m)Tc(CO)3 complex was more lipophilic than previously reported 2-nitroimidazole-DETA-(99m)Tc(CO)3 complex (DETA-diethylenetriamine) and showed slower blood clearance. Consequently it showed higher tumor uptake than 2-nitroimidazole-DETA-(99m)Tc(CO)3 complex. Significantly, despite structural modifications, other parameters such as the tumor to blood ratio and tumor to muscle ratio of the 2-nitroimidazole-DPA-(99m)Tc(CO)3 complex remained comparable to that of 2-nitroimidazole-DETA-(99m)Tc(CO)3 complex. Present study demonstrates the feasibility of structural modifications for improving in vivo tumor uptake of hypoxia detecting radiopharmaceuticals. This might encourage researchers to improve suboptimal properties of a potential radiopharmaceuticals rather than ignoring it altogether.
authors.affiliation: Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Madhava B
authors.initials: MB
authors.lastname: Mallia
authors.affiliation: Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Sweety
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Radiation Biology and Health Science Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Haladhar D
authors.initials: HD
authors.lastname: Sarma
authors.affiliation: Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, Mumbai 400085, India. Electronic address: sharmila@barc.gov.in.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000097:blood / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: C000609211:(99m)Tc(CO)3-2-nitroimidazole-dipicolylamine; D002614:Chelating Agents; D008024:Ligands; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals
keywords: (99m)Tc(CO)(3) core; 2-Nitroimidazole; Dipicolylamine; Fibrosarcoma; Hypoxia; Modulation of biodistribution