In vitro evaluation of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-trifluoromethylquinoline hydrochloride (NLTQ-1), a new bioreductive agent as a hypoxia marker by 19F-magnetic resonance spectroscopy (19F-MRS).
19F-labeled bioreductive drugs bound to hypoxic cells in tumors could be detected by nuclear magnetic resonance, provided that they do not lose 19F during their metabolism. NLTQ-1, a 2-nitroimidazole-linked 7-trifluoromethylquinoline, has been synthesized to furnish this aim. NLTQ-1 demonstrated hypoxic selectivities of 7-10 in various cell-lines, in vitro. Uptake studies in V79 cells showed a 5 to 6 fold greater intracellular than extracellular concentration at a range of 100-300 microM input concentrations. A strong sharp peak, which was identified as the parent compound, was observed in the 19F-NMR spectrum of 90% MeCN extracts of V79 cells aerobically exposed to NLTQ-1, indicating that NLTQ-1 was not metabolized under aerobic conditions. Similarly, 19F NMR efflux studies in intact cells showed that the NLTQ-1 was bound to the cells predominantly under hypoxic conditions. 19F-NMR spectra of intact cells, exposed under hypoxic conditions to NLTQ-1, and of their lysates, after precipitation of various cellular components, indicated that possible covalent binding of NLTQ-1 had occurred with macromolecules such as proteins and nucleic acids. Therefore, NLTQ-1 might be suitable as a 19F-MRS/MRI hypoxia probe, although further in vivo work is necessary to verify this matter.
Papadopoulou
M V
MV
Department of Radiation Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA. m-papadopoulou@nwu.edu
Pouremad
R
R
Rao
M K
MK
Ji
M
M
Bloomer
W D
WD
D000332:Aerobiosis; D000818:Animals; D002458:Cell Fractionation; D015687:Cell Hypoxia; D002460:Cell Line / Q000737:chemistry / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D005110:Extracellular Space / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects; D005461:Fluorine / Q000032:analysis*; D006801:Humans; D007093:Imidazoles / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007424:Intracellular Fluid / Q000737:chemistry; D007554:Isotopes / Q000032:analysis; D008168:Lung / Q000166:cytology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000473:pathology; D011485:Protein Binding; D011804:Quinolines / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D019163:Reducing Agents / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects
C451960:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-trifluoromethylquinoline hydrochloride; D007093:Imidazoles; D007554:Isotopes; D011804:Quinolines; D019163:Reducing Agents; D005461:Fluorine; D004247:DNA