The accumulation mechanism of the hypoxia imaging probe “FMISO” by imaging mass spectrometry: possible involvement of low-molecular metabolites

Masaki, Yukiko; Shimizu, Yoichi; Yoshioka, Takeshi; Tanaka, Yukari; Nishijima, Ken‐ichi; Zhao, Shen; Higashino, Kenichi; Sakamoto, Shingo; Numata, Yoshito; Yamaguchi, Yoshitaka; Tamaki, Nagara; Kuge, Yuji

doi:10.1038/srep16802

Cited by 64 publications

(69 citation statements)

References 25 publications

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“…In that study, we demonstrated that most of the radioactivity derived from 18 F-FMISO was present in low-molecular-weight substances in hypoxic tumors. This was in contrast to observations made with conventional views of FMISO covalent binding to macromolecules, and a glutathione conjugate of reduced FMISO (amino-FMISO) was a component responsible for FMISO accumulation in the hypoxic regions of tumors [13]. This result suggests that 18 F-FMISO incorporated in hypoxic cells is conjugated with glutathione following reduction of its nitro group, and thus the radioactivity was trapped in the cells.…”

Section: Introductioncontrasting

confidence: 79%

Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent “Pimonidazole” in Hypoxia

et al. 2016

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Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole-based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group. However, the detailed mechanism of its accumulation remains unknown. In this study, we investigated the accumulation mechanism of pimonidazole in hypoxic tumor tissues in a mouse model by mass spectrometric analyses including imaging mass spectrometry (IMS). Pimonidazole and its reductive metabolites were observed in the tumor tissues. However, their locations in the tumor sections were not similar to the positively stained areas in pimonidazole-immunohistochemistry, an area considered hypoxic. The glutathione conjugate of reduced pimonidazole, a low-molecular-weight metabolite of pimonidazole, was found in tumor tissues by LC-MS analysis, and our IMS study determined that the intratumor localization of the glutathione conjugate was consistent with the area positively immunostained for pimonidazole. We also found complementary localization of the glutathione conjugate and reduced glutathione (GSH), implying that formation of the glutathione conjugate occurred in the tumor tissue. These results suggest that in hypoxic tumor cells, pimonidazole is reduced at its nitro group, followed by conjugation with GSH.

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Section: Introductioncontrasting

confidence: 79%

Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent “Pimonidazole” in Hypoxia

et al. 2016

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“…[ 18 F]-FMISO freely diffuses into cells and under normal oxidative conditions, freely exits. When entering hypoxic cells, FMISO is reduced and retained through accumulation of the 2-nitroimidazole metabolites and irreversible binding to intracellular thiol-rich proteins [17]. The retention of the tracer in hypoxic tissue makes [ 18 F]-FMISO-PET a highly sensitive and specific, noninvasive imaging technique for detection of tumors that exhibit hypoxia [18-19].…”

Section: Introductionmentioning

confidence: 99%

Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

et al. 2016

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Purpose Evaluation of [18F]-FMISO-PET imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer. Procedures Mice with BT474, HER2+ tumors, were imaged with [18F]-FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging. Results [18F]-FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r2=0.85). Conclusions [18F]-FMISO-PET is a clinically relevant modality which provides the opportunity to 1) predict response to HER2+ therapy before changes in tumor size, and 2) identify decreases hypoxia which has the potential to guide subsequent therapy.

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“…The best example is 18 F-fluoromisonidazole (FMISO), which undergoes chemical transformation in tissues with low oxygen tension, with multiple reductions resulting in species capable of covalent binding to macromolecules, or conjugation to reduced glutathione (GSH)(12). These transformations are shown in Figure 2, as is a FMISO scan demonstrating the effects of radiation therapy on a brain tumor(13).…”

Section: Pet Tracers- General Strategiesmentioning

confidence: 99%

Exploring Metabolism In Vivo Using Endogenous 11 C Metabolic Tracers

Neumann

Flavell

Wilson

2017

Seminars in Nuclear Medicine

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Cancer and other diseases are increasingly understood in terms of their metabolic disturbances. This thinking has revolutionized the field of ex vivo metabolomics and motivated new approaches to detect metabolites in living systems including proton magnetic resonance spectroscopy (1H-MRS), hyperpolarized 13C MRS, and positron emission tomography (PET). For PET, imaging abnormal metabolism in vivo is hardly new. Positron-labeled small-molecule metabolites have been used for decades in humans, including 18F-FDG, which is used frequently to detect upregulated glycolysis in tumors. Many current 18F metabolic tracers including 18F-FDG have evolved from their 11C counterparts, chemically identical to endogenous substrates and thus approximating intrinsic biochemical pathways. This mimicry has stimulated the development of new radiochemical methods to incorporate 11C and inspired the synthesis of a large number of 11C endogenous radiotracers. This is in spite of the 20-minute half-life of 11C, which generally limits its use in patients to centers with an on-site cyclotron. Innovation in 11C chemistry has persisted in the face of this limitation, because (1) the radiochemists involved are inspired (2) the methods of 11C incorporation are diverse and (3) 11C compounds often show more predictable in vivo behavior, thus representing an important first step in the validation of new tracer concepts. In this mini-review we will discuss some of the general motivations behind PET tracers, rationales for the use of 11C, and some of the special challenges encountered in the synthesis of 11C endogenous compounds. Most importantly, we will try to highlight the exceptional creativity employed in early 11C tracer syntheses, which used enzyme-catalyzed and other “green” methods before these concepts were commonplace.

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The accumulation mechanism of the hypoxia imaging probe “FMISO” by imaging mass spectrometry: possible involvement of low-molecular metabolites

Cited by 64 publications

References 25 publications

Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent “Pimonidazole” in Hypoxia

Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent “Pimonidazole” in Hypoxia

Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Exploring Metabolism In Vivo Using Endogenous 11 C Metabolic Tracers

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