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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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IRDye800-2-Deoxy-D-glucose

IRDye800-2-DG
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: July 24, 2009.

Chemical name:IRDye800-2-Deoxy-D-glucose
Abbreviated name:IRDye800-2-DG
Synonym:
Agent category:Compound
Target:Glucose transporters, hexokinases
Target category:Transporter, enzyme
Method of detection:Optical, near-infrared fluorescence (NIR) imaging
Source of signal:IRDye800
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure is available in PubChem.

Background

[PubMed]

Optical fluorescence imaging is increasingly being used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. NIR fluorophores also have high sensitivity, attributable to low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a non-invasive complement to radionuclide imaging in small animals.

The phosphorylation of glucose, an initial and important step in cellular metabolism, is catalyzed by hexokinases (HKs) (4). There are four HKs in mammalian tissues (HKI–HKIV). HKI, HKII, and HKIII have molecular weights of ~100,000 each; HKI is found mainly in the brain, and HKII is insulin-sensitive and is found in adipose and muscle cells. HKIV, also known as glucokinase, has a molecular weight of 50,000 and is specific to the liver and pancreas. Most brain HK is bound to mitochondria, enabling coordination between glucose consumption and oxidation. Tumor cells are known to be highly glycolytic because of increased expression of glycolytic enzymes and HK activity (5), which was detected in tumors from patients with lung, gastrointestinal, and breast cancers. The HKs, by converting glucose to glucose-6-phosphate, help maintain the downhill gradient that results in the transport of glucose into cells through the facilitative glucose transporters (GLUT1–13) (6). GLUT4 and HKII are the major transporters and HK isoforms in skeletal muscle, heart, and adipose tissue, wherein insulin promotes glucose utilization. HKIV is associated with GLUT2 in liver and pancreatic β cells.

2-Deoxy-d-glucose (2-DG) was first developed to inhibit glucose utilization by cancer cells (7). HKs phosphorylate 2-DG to 2-DG-6-phosphate, which inhibits phosphorylation of glucose. 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) was later developed for molecular imaging studies (8). FDG is moved into cells by glucose transporters and is then phosphorylated by HK to FDG-6-phosphate. FDG-6-phosphate cannot be metabolized further in the glycolytic pathway and remains in the cells. Tumor cells do not contain a sufficient amount of glucose-6-phosphatase to reverse the phosphorylation. The elevated rates of glycolysis and glucose transport in many types of tumor cells and activated cells enhance the uptake of FDG in these cells relative to other normal cells. Positron emission tomography (PET) with [18F]FDG has been used to assess alterations in glucose metabolism in brain, cancer, cardiovascular diseases, Alzheimer’s disease and other central nervous system disorders, and infectious, autoimmune, and inflammatory diseases (9-14). Kovar et al. (15) developed a NIR-labeled 2-DG (IRDye800-2-DG) with IRDye800 by conjugation of IRDye800 to 2-amino-2-DG. IRDye800-2-DG is being evaluated as an optical imaging agent for in vivo imaging of tumors in mice.

Synthesis

[PubMed]

IRDye800CW-N-Hydroxysuccinimide ester (LI-COR, Lincoln, NE) was reacted with 2-amino-2-DG for 2 h at room temperature in 1 M potassium phosphate buffer (pH 8.5) (15). IRDye800-2-DG was purified with high-performance liquid chromatography and verified with NMR spectroscopy.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro uptake studies of IRDye800-2-DG were performed with A431, 3T3-L1, and 22Rv1 cells in culture showing that high, medium, and low NIR fluorescence intensity correlated with their metabolic activity, respectively (15). Monoclonal antibody against GLUT1, d-glucose, or 2-DG was able to block the uptake of IRDye800-2-DG in a dose-dependent manner. Fluorescence microscopy showed that IRDye800-2-DG accumulated in the cytoplasm of several tumor cells (M21-L melanoma and MDA-MB-231 breast carcinoma cell lines) but was not localized in the cell surface and nucleus. Excess 2-DG was able to block the NIR fluorescence signal in the cytoplasm.

Animal Studies

Rodents

[PubMed]

Kovar et al. (15) performed in vivo NIR fluorescence imaging studies of IRDye800-2-DG and IRDye800 (20 nmol per mouse) in mice bearing VEGFR-2–expressing 22Rv1 xenografts. Sagittal images were obtained at 18, 24, 30, 42, and 72 h after intravenous injection. IRDye800-2-DG exhibited peak signal intensity at 18 h with a gradual washout. There was a four-fold increase in signal over IRDye800 at 24 h after injection. Ex vivo NIR fluorescence images of various organs were obtained at 24 and 36 h after injection. IRDye800-2-DG exhibited NIR intensities one to three times higher than did IRDye800 in the kidney, lung, muscle, and liver at 24 h. The brain, spleen, intestine, and heart exhibited only background signal. All organs showed minimal NIR intensities by 36 h with either IRDye800-2-DG or IRDye800 injection, whereas the tumor showed ~1-fold higher signal with IRDye800-2-DG injection compared with IRDye800 injection. Other tumor xenografts showed varied uptake dependent on cellular origin of the tumors at 24 h after injection. No blocking experiment was performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Achilefu S. Lighting up tumors with receptor-specific optical molecular probes. Technol Cancer Res Treat. 2004;3(4):393–409. [PubMed: 15270591]
2.
Ntziachristos V., Bremer C., Weissleder R. Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging. Eur Radiol. 2003;13(1):195–208. [PubMed: 12541130]
3.
Becker A., Hessenius C., Licha K., Ebert B., Sukowski U., Semmler W., Wiedenmann B., Grotzinger C. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands. Nat Biotechnol. 2001;19(4):327–31. [PubMed: 11283589]
4.
Smith T.A. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57(2):170–8. [PubMed: 10912295]
5.
Suolinna E.M., Haaparanta M., Paul R., Harkonen P., Solin O., Sipila H. Metabolism of 2-[18F]fluoro-2-deoxyglucose in tumor-bearing rats: chromatographic and enzymatic studies. Int J Rad Appl Instrum B. 1986;13(5):577–81. [PubMed: 3818323]
6.
Avril N. GLUT1 expression in tissue and (18)F-FDG uptake. J Nucl Med. 2004;45(6):930–2. [PubMed: 15181126]
7.
Laszlo J., Humphreys S.R., Goldin A. Effects of glucose analogues (2-deoxy-D-glucose, 2-deoxy-D-galactose) on experimental tumors. J Natl Cancer Inst. 1960;24:267–81. [PubMed: 14414406]
8.
Fowler J.S., Ido T. Initial and subsequent approach for the synthesis of 18FDG. Semin Nucl Med. 2002;32(1):6–12. [PubMed: 11839070]
9.
Phelps M.E. PET: the merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41(4):661–81. [PubMed: 10768568]
10.
Phelps M.E., Mazziotta J.C. Positron emission tomography: human brain function and biochemistry. Science. 1985;228(4701):799–809. [PubMed: 2860723]
11.
Phelps M.E., Mazziotta J.C., Huang S.C. Study of cerebral function with positron computed tomography. J Cereb Blood Flow Metab. 1982;2(2):113–62. [PubMed: 6210701]
12.
Rohren E.M., Turkington T.G., Coleman R.E. Clinical applications of PET in oncology. Radiology. 2004;231(2):305–32. [PubMed: 15044750]
13.
Sokoloff L. Basic principles in imaging of regional cerebral metabolic rates. Res Publ Assoc Res Nerv Ment Dis. 1985;63:21–49. [PubMed: 2992057]
14.
Spence A.M., Mankoff D.A., Muzi M. Positron emission tomography imaging of brain tumors. Neuroimaging Clin N Am. 2003;13(4):717–39. [PubMed: 15024957]
15.
Kovar J.L., Volcheck W., Sevick-Muraca E., Simpson M.A., Olive D.M. Characterization and performance of a near-infrared 2-deoxyglucose optical imaging agent for mouse cancer models. Anal Biochem. 2009;384(2):254–62. [PMC free article: PMC2720560] [PubMed: 18938129]
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