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- Title
A Novel PET Probe "[<sup>18</sup>F]DiFA" Accumulates in Hypoxic Region via Glutathione Conjugation Following Reductive Metabolism.
- Authors
Shimizu, Yoichi; Zhao, Songji; Yasui, Hironobu; Nishijima, Ken-ichi; Matsumoto, Hiroki; Shiga, Tohru; Tamaki, Nagara; Ogawa, Mikako; Kuge, Yuji
- Abstract
<bold>Purpose: </bold>Hypoxia in tumor has close relationship with angiogenesis and tumor progression. Previously, we developed 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) as a novel positron emission tomography (PET) probe for diagnosis of hypoxia. In this study, we elucidated whether the accumulation of [18F]DiFA in cells is dependent on the hypoxic state and revealed how [18F]DiFA accumulates in hypoxic cells in combination with imaging mass spectrometry (IMS).<bold>Procedures: </bold>FaDu human head and neck cancer cells were treated with [18F]DiFA and then incubated under normoxia (21% O2) or hypoxia (1% O2) for 2 h. The cells were extracted using methanol, and the radioactivities of the precipitates (macromolecule fraction) and supernatants (low-molecular-weight fraction) were measured. FaDu-bearing mice were injected intravenously with [18F]DiFA and with pimonidazole 1 h later. The tumors were excised 2 h after the injection of [18F]DiFA. Autoradiography, IMS, and immunohistochemical (IHC) staining for pimonidazole were performed with serial tumor sections.<bold>Results: </bold>In the in vitro study, the radioactivity of FaDu cells was significantly higher under hypoxia than that under normoxia (0.53 ± 0.02 vs. 0.27 ± 0.02 %dose/mg protein, p < 0.05). The radioactivity of the low-molecular-weight fraction was 66.3 ± 0.6% in the hypoxic cell. In the in vivo study, [18F]DiFA accumulated in the tumor tissues existed mainly as low-molecular-weight compounds (90.4 ± 0.9%). In addition, the glutathione conjugate of reductive DiFA metabolite (amino-DiFA-GS) existed in tumor tissues revealed by the IMS study, and the distribution pattern of amino-DiFA-GS was very similar to that of the radioactivity and the positive staining area of pimonidazole.<bold>Conclusions: </bold>Our results suggest that [18F]DiFA undergoes the glutathione conjugation reaction following reductive metabolism in hypoxic cells, which leads hypoxia-specific PET imaging with [18F]DiFA.
- Subjects
HYPOXEMIA; GLUTATHIONE; CANCER invasiveness; NEOVASCULARIZATION; POSITRON emission tomography; NITROIMIDAZOLES
- Publication
Molecular Imaging & Biology, 2019, Vol 21, Issue 1, p122
- ISSN
1536-1632
- Publication type
journal article
- DOI
10.1007/s11307-018-1214-y