Hypoxia imaging can guide tumor treatment
and monitor changes in
hypoxia during treatment. However, there is still no ideal hypoxia
imaging agent for clinical applications. In this study, two novel
2-nitromidazole derivatives were synthesized and directly radiolabeled
by [18F]FDG in high radiochemical yield and excellent radiochemical
purity. Cell experiments, biodistribution, and positron emission tomography
(PET) imaging studies were also conducted in mice-bearing S180 or
OS732 tumors. [18F]FDG-2NNC2ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [18F]FDG-2NNC5ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1H-imidazole-1-yl)pentylamino)-2-oxopropyl oxime] can be
cleared from the blood quickly and specifically target hypoxic tumor
cells. The uptake of the probes by hypoxic cells gradually increases
with time. After 4 h, the uptake value of [18F]FDG-2NNC2ON
in hypoxic cells is 3.2 times higher than that in normoxia cells.
In contrast, there is no difference in the uptake of [18F]FDG between hypoxic cells and normoxia cells. Biodistribution resulting
from two tumor models indicate that the uptake values of the two radiotracers
in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2
h, the tumors are clearly observed on the PET images and the imaging
features of [18F]FDG-2NNC5ON and [18F]FDG-2NNC2ON
are distinct from those of [18F]FDG. Compared with [18F]FDG-2NNC5ON, [18F]FDG-2NNC2ON has a higher proportion
of renal excretion, lower digestive tract uptake, and better imaging
contrast because of its higher hydrophilicity. At 2 h, [18F]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle
ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle
ratio based on regions of interest on the PET images [region of interest
(ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M
ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4,
4.2, and 4.6 in the OS732 tumor model, respectively). The imaging
features visualized with autoradiography mostly coincided with the
positive areas of HIF1α staining by immunofluorescence. Meanwhile,
the biodistribution study and PET imaging revealed that the uptake
of the radiotracers in the tumor cannot be competed by 5% glucose,
confirming that [18F]FDG-2NNC2ON targets the hypoxic regions
of the tumors instead of targeting tumors through the glucose metabolism
pathway. These results suggest that the new 2-nitroimidazole derivative
conjugated with [18F]FDG, [18F]FDG-2NNC2ON,
has potential as an imaging agent for hypoxia.