title: Targeting hypoxia in tumors using 2-nitroimidazoles with peptidic chelators for technetium-99m: effect of lipophilicity.
abstract: Tumor hypoxia is an important prognostic factor for response to therapy. Radiolabeled 2-nitroimidazoles have been used for imaging hypoxia, and the octanol/water partition coefficient (P) of these compounds appears to play a crucial role in their suitability for imaging. A series of 11 2-nitroimidazoles coupled to peptidic chelators for (99m)Tc with divergent P was developed and evaluated in an in vitro system. Two classes of N(3)S chelators were used: dialkyl-Gly-Ser-Cys-linker-2-nitroimidazole (Class I) and dialkyl-Gly-Lys(2-nitroimidazole)-Cys (Class II). The chelators were prepared by automated solid-phase peptide synthesis. Xanthine oxidase was able to reduce the 2-nitroimidiazole moiety on the ligands, but the rate of reduction varied 5-fold among the different chelators. The chelators were labeled by transchelation from [(99m)Tc]gluconate at temperatures between 22 and 100 degrees C. The reaction mixtures were analyzed by HPLC and their P values determined. The accumulation of each complex in suspension cultures of Chinese hamster ovary cells incubated under aerobic or extremely hypoxic conditions was determined. Radiochemical yields ranged from 5 to 80% for the 11 compounds. HPLC showed that some of the compounds formed two complexes with (99m)Tc, possibly syn and anti conformations with respect to the Tc=O bond. In general, the Class I chelators labeled more readily than the class II chelators. The P values of the (99m)Tc complexes varied from 0.0002 to 5 and were generally in accordance with predictions based on structure. There were also differences in P as a function of pH; the free acids had a lower P at pH 7.4 than at pH 2.0 due to ionization, whereas the amides did not show this effect. Accumulation levels in aerobic cells were related to P but varied over a narrow range. Four of the 11 compounds showed selective accumulation in hypoxic cells. The peptidic class of 2-nitroimidazoles, with flexible design and convenient solid-phase synthesis, deserves further study as agents for imaging hypoxia in tumors.
authors.affiliation: Division of Experimental Therapeutics, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: Z F
authors.initials: ZF
authors.lastname: Su
authors.forename: J R
authors.initials: JR
authors.lastname: Ballinger
authors.forename: A M
authors.initials: AM
authors.lastname: Rauth
authors.forename: A
authors.initials: A
authors.lastname: Pollak
authors.forename: J R
authors.initials: JR
authors.lastname: Thornback
mesh_terms: D000818:Animals; D016466:CHO Cells; D015687:Cell Hypoxia; D002614:Chelating Agents; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000150:complications*; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013667:Technetium; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: C411330:5-acetamido-2-((N,N-dimethylaminomethylamido)(((2-nitroimidazol-1-yl)methylamido)butyl)acetamido)-4-thiapentanoic acid; D002614:Chelating Agents; D008055:Lipids; D009593:Nitroimidazoles; D013667:Technetium; D014969:Xanthine Oxidase; D008239:Lysine