title: The accumulation mechanism of the hypoxia imaging probe "FMISO" by imaging mass spectrometry: possible involvement of low-molecular metabolites.
abstract: (18)F-fluoromisonidazole (FMISO) has been widely used as a hypoxia imaging probe for diagnostic positron emission tomography (PET). FMISO is believed to accumulate in hypoxic cells via covalent binding with macromolecules after reduction of its nitro group. However, its detailed accumulation mechanism remains unknown. Therefore, we investigated the chemical forms of FMISO and their distributions in tumours using imaging mass spectrometry (IMS), which visualises spatial distribution of chemical compositions based on molecular masses in tissue sections. Our radiochemical analysis revealed that most of the radioactivity in tumours existed as low-molecular-weight compounds with unknown chemical formulas, unlike observations made with conventional views, suggesting that the radioactivity distribution primarily reflected that of these unknown substances. The IMS analysis indicated that FMISO and its reductive metabolites were nonspecifically distributed in the tumour in patterns not corresponding to the radioactivity distribution. Our IMS search found an unknown low-molecular-weight metabolite whose distribution pattern corresponded to that of both the radioactivity and the hypoxia marker pimonidazole. This metabolite was identified as the glutathione conjugate of amino-FMISO. We showed that the glutathione conjugate of amino-FMISO is involved in FMISO accumulation in hypoxic tumour tissues, in addition to the conventional mechanism of FMISO covalent binding to macromolecules.
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Masaki
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Sapporo 060-0815, Japan.|Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Shionogi Pharmaceutical Research Center, Research Laboratory for Development, Shionogi &Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Nishijima
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.affiliation: Shionogi Pharmaceutical Research Center, Research Laboratory for Development, Shionogi &Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Numata
authors.affiliation: Shionogi Pharmaceutical Research Center, Research Laboratory for Development, Shionogi &Co., Ltd., Osaka 561-0825, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Sapporo 060-0815, Japan.|Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
mesh_terms: D000818:Animals; D003952:Diagnostic Imaging / Q000379:methods*; D000860:Hypoxia / Q000000981:diagnostic imaging*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D055442:Metabolome; D055432:Metabolomics; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D015335:Molecular Probes / Q000378:metabolism*; D008970:Molecular Weight; D009369:Neoplasms / Q000000981:diagnostic imaging; D011877:Radionuclide Imaging; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D015335:Molecular Probes; C031843:fluoromisonidazole; D008920:Misonidazole