title: Synthesis, in vitro and in vivo characterization of novel 99mTc-'4+1'-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia.
abstract: The evaluation of oxygenation status of solid tumors is an important field of radiopharmaceutical research. With the aim to develop new potential 99mTc-radiopharmaceuticals for imaging hypoxia, we have synthesized two novel isocyanide derivatives of metronidazole, which has demonstrated high affinity for hypoxic tumors in vitro and in vivo.
  
  
  METHODS
  Metronidazole derivatives 4-isocyano-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]butanamide (M1) and 1-(4-isocyanobutanoyl)-4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]piperazine (M2) were synthesized, and labeling was performed through preparation of their corresponding 99mTc-(4+1) complexes, 99mTc-NS3M1 and 99mTc-NS3M2. The structure of the technetium complexes was corroborated by preparation and characterization of the corresponding rhenium complexes. We have studied the main physicochemical properties (stability, lipophilicity and plasma protein binding). Biological behavior in HCT-15 cells both in oxia and in hypoxia was assessed. Biodistribution in normal mice and in animals bearing induced 3LL Lewis murine lung carcinoma was also studied.
  
  
  RESULTS
  Metronidazole derivatives were successfully synthesized. Labeling with high radiochemical purity was achieved for both ligands. 99mTc complexes were stable in labeling milieu and human plasma. However, presence of the piperazine linker in M2 resulted in higher lipophilicity and protein binding. Although cell uptake in hypoxic conditions was observed for both radiotracers, 99mTc-NS3M2 biodistribution was considered unsuitable for a potential radiopharmaceutical due to high liver uptake and poor blood clearance. However, 99mTc-NS3M1 demonstrated a very favorable in vivo profile both in normal mice and in mice bearing induced tumors.
  
  
  CONCLUSIONS
  Selective uptake and retention in tumor together with favorable tumor/muscle ratio make 99mTc-NS3M1 a promising candidate for further evaluation as potential hypoxia imaging agent in tumors.
authors.affiliation: Cátedra de Radioquímica, Facultad de Química, UdelaR, Montevideo, Uruguay.
authors.forename: Javier
authors.initials: J
authors.lastname: Giglio
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernández
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dematteis
authors.forename: María
authors.initials: M
authors.lastname: Moreno
authors.forename: José P
authors.initials: JP
authors.lastname: Pacheco
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Ana
authors.initials: A
authors.lastname: Rey
mesh_terms: D000818:Animals; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D009593:Nitroimidazoles / Q000737:chemistry*; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D012211:Rhenium / Q000737:chemistry
chemical_list: D001798:Blood Proteins; D008024:Ligands; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D012211:Rhenium; C052587:4-nitroimidazole