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Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe
Author(s) -
RojasQuijano Federico A.,
Tircsó Gyula,
Tircsóné Benyó Enikő,
Baranyai Zsolt,
Tran Hoang Huan,
Kálmán Ferenc K.,
Gulaka Praveen K.,
Kodibagkar Vikram D.,
Aime Silvio,
Kovács Zoltán,
Sherry A. Dean
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200266
Subject(s) - nitroimidazole , chemistry , amide , gadolinium , hypoxia (environmental) , oxygen , tumor hypoxia , dota , radiosynthesis , proton nmr , nuclear magnetic resonance , stereochemistry , chelation , nuclear medicine , biochemistry , organic chemistry , medicine , physics , positron emission tomography , radiation therapy
Abstract Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T 1 relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA) − as expected for mono‐amide derivatives. The water proton T 1 relaxivity ( r 1 ), bound water residence lifetime ( τ M ) and rotational correlation time ( τ R ) of both complexes was determined by relaxivity measurements, variable temperature 17 O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters ( r 1 =6.38 m M −1 s −1 at 20 MHz , τ M =0.71 μs, τ R =141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N 2 as evidenced by an approximately twofold decrease in T 1 measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.