Synthesis and Characterization of a Hypoxia-Sensitive MRI Probe

Rojas-Quijano, Federico A. and Tircsó, Gyula and Tircsóné Benyó, Enikő and Baranyai, Zsolt and Tran Hoang, Huan and Kálmán, Ferenc Krisztián and Gulaka, Praveen K. and Kodibagkar, Vikram D. and Aime, Silvio and Kovács, Zoltán and Sherry, A. Dean (2012) Synthesis and Characterization of a Hypoxia-Sensitive MRI Probe. Chemistry - European Journal, 18 (31). pp. 9669-9676.

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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 complex of 1,4,7,10-tetraaza-1,4,7,10-tetraacetate (DOTA) having 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 (r1), bound water residence lifetime M) and rotational correlation time (τR) of both complexes was determined by relaxivity measurements, variable temperature 17O NMR and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r1 = 6.38 mм–1s–1 at 20 MHz, M = 0.71 s, R = 141 ps) determined for the nitroimidazole derivative closely parallel those of other Gd(DO3A-monoamide) complexes of similar molecular size. In vitro MR imaging experiments using 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative is trapped in cells maintained under N2 as evidenced by ~2-fold decrease in T1 measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative may serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD01 Analytical chemistry / analitikai kémia
Q Science / természettudomány > QD Chemistry / kémia > QD02 Physical chemistry / fizikai kémia
Q Science / természettudomány > QD Chemistry / kémia > QD03 Inorganic chemistry / szervetlen kémia
Depositing User: Dr Tircsó Gyula
Date Deposited: 20 Sep 2014 16:09
Last Modified: 12 May 2016 10:56

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