TY - JOUR
T1 - Synthesis and characterization of a hypoxia-sensitive MRI probe
AU - Rojas-Quijano, Federico A.
AU - Tircsõ, Gyula
AU - Tircsõné Benyõ, Enikó
AU - Baranyai, Zsolt
AU - Tran Hoang, Huan
AU - Kálmán, Ferenc K.
AU - Gulaka, Praveen K.
AU - Kodibagkar, Vikram D.
AU - Aime, Silvio
AU - Kovács, Zoltán
AU - Sherry, A. Dean
PY - 2012/7/27
Y1 - 2012/7/27
N2 - 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 T1 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 T1 relaxivity (r 1), bound water residence lifetime (τM) and rotational correlation time (τR) of both complexes was determined by relaxivity measurements, variable temperature 17O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r1=6.38 mM-1 s-1 at 20 MHz, τM=0.71 μs, τR=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 N2 as evidenced by an approximately twofold decrease in T1 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. Hunting hypoxic cells: The DO3A-monoamide ligand with a 2-nitroimidazole moiety was synthesized with an aim to complex the Gd III ion as well as to target and visualize hypoxic cells by using the MRI technique (see figure). In vitro MRI experiments revealed that the conjugate might be suitable for assessment of hypoxia in vivo as the agent was selectively trapped in hypoxic (9L rat glioma) cells.
AB - 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 T1 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 T1 relaxivity (r 1), bound water residence lifetime (τM) and rotational correlation time (τR) of both complexes was determined by relaxivity measurements, variable temperature 17O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r1=6.38 mM-1 s-1 at 20 MHz, τM=0.71 μs, τR=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 N2 as evidenced by an approximately twofold decrease in T1 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. Hunting hypoxic cells: The DO3A-monoamide ligand with a 2-nitroimidazole moiety was synthesized with an aim to complex the Gd III ion as well as to target and visualize hypoxic cells by using the MRI technique (see figure). In vitro MRI experiments revealed that the conjugate might be suitable for assessment of hypoxia in vivo as the agent was selectively trapped in hypoxic (9L rat glioma) cells.
KW - imaging agents
KW - imaging of hypoxic tissue
KW - ligand design
KW - relaxation properties
KW - stability
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U2 - 10.1002/chem.201200266
DO - 10.1002/chem.201200266
M3 - Article
C2 - 22740186
AN - SCOPUS:84864144412
SN - 0947-6539
VL - 18
SP - 9669
EP - 9676
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 31
ER -