• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

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

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

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

Show details

99mTc-Ethylenedicysteine-deoxyglucose

99mTc-EC-DG
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: February 16, 2010.

Chemical name:99mTc-Ethylenedicysteine-deoxyglucoseimage 87225209 in the ncbi pubchem database
Abbreviated name:99mTc-EC-DG, 99mTc-ECDG
Synonym:99mTc-Ethylenedicysteine-D-glucosamine
Agent category:Compound
Target:Glucose transporters, hexokinases
Target category:Transporter, enzyme
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on the above structure for additional information 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 alternative to radionuclide imaging in small animals (4, 5).

The phosphorylation of glucose, an initial and important step in cellular metabolism, is catalyzed by hexokinases (HKs) (6). 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 (7), which have been 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) (8). 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 (9). 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 (10). 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 with [18F]FDG has been used to assess alterations in glucose metabolism in the brain, cancer, cardiovascular diseases, Alzheimer’s disease and other central nervous system disorders, as well as infectious, autoimmune, and inflammatory diseases (11-16). Glucosamine and FDG have the amino and fluorine group at position 2 of the sugar, and they are taken up in cells by glucose transporters. Yang et al. (17) developed 99mTc-ethylenedicysteine-deoxyglucose (99mTc-EC-DG) by conjugation of two D-glucosamine (2-amino-deoxyglucose) molecules to ethylenedicysteine for single-photon emission computed tomography (SPECT) imaging activity of glucose transporters and hexokinases in tumors.

Synthesis

[PubMed]

EC and glucosamine (1:4 molar ratio) were incubated in the presence of sodium hydroxide, sulfo-N-hydroxysuccinimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide for 24 h at room temperature (17). EC-DG was isolated from the incubation mixture with dialysis. The structure of EC-DG was verified with mass spectroscopy and nuclear magnetic resonance spectroscopy. EC-DG (50 mg) was mixed with 1.1–1.4 MBq (40–50 mCi) 99mTc-pertechnetate and SnCl2. 99mTc-EC-DG had a radiochemical purity of 96% and a specific activity of 18.5 GBq/mmol (0.5 Ci/mmol). 99mTc-EC-DG was stable in dog serum for 0.5–24 h of incubation at 37°C.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro uptake studies of 99mTc-EC-DG and [18F]FDG were performed with human lung tumor A549 cells in culture showing 0.5% and 0.6% incubation dose at 4 h of incubation, respectively. d-Glucose was able to block the uptake of 99mTc-EC-DG in a dose-dependent manner. On the other hand, l-glucose showed no inhibition of the uptake. EC-DG was shown to be phosphorylated in a hexokinase assay. 99mTc-EC-DG showed little effect on [3H]thymidine incorporation into the A549 cells (18).

Animal Studies

Rodents

[PubMed]

Yang et al. (17) performed ex vivo biodistribution studies of 99mTc-EC-DG and [18F]FDG in mice (n = 3/group) bearing A549 xenografts at 0.5 h, 2 h, and 4 h after injection. The accumulation of radioactivity of 99mTc-EC-DG in the tumors was 0.79 ± 0.16% of injected dose per gram (% ID/g) at 0.5 h, 0.42 ± 0.12% ID/g at 2 h, and 0.41 ± 0.16% ID/g at 4 h after injection. The liver had the highest accumulation (5.81% ID/g), followed by the kidney (5.69% ID/g) and spleen (4.21% ID/g) at 2 h after injection. Accumulation of radioactivity in the brain (0.04% ID/g) was low. The concentration in the blood was 1.0% ID/g at 2 h after injection. The tumor/blood, tumor/muscle, and tumor/lung ratios were 0.42, 2.75, and 0.59 at 2 h after injection, respectively. The accumulation of radioactivity of [18F]FDG in the tumors was 2.23 ± 0.15% ID/g at 0.5 h, 1.70 ± 0.17% ID/g at 2 h, and 1.61 ± 0.18% ID/g at 4 h after injection. 99mTc-EC-DG exhibited higher tumor/muscle and tumor/brain ratios than [18F]FDG. On the other hand, [18F]FDG exhibited a higher tumor/blood ratio than 99mTc-EC-DG, with no difference in the tumor/lung ratio. Scintigraphy images were obtained in rats bearing breast tumors at 1, 30, and 120 min after intravenous injection of 99mTc-EC-DG. The smallest tumor size that could be visualized was 3 mm. The tumor/muscle ratios were 1.70, 1.58, and 1.82 for the small tumors and 2.36, 2.41, and 2.88 for the medium tumors at the time points, respectively. Pretreatment with FDG decreased the tumor/muscle ratios by 40%, whereas pretreatment with insulin increased the tumor/muscle ratios by 60%. Little tumor accumulation was observed with 99mTc-EC.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Human dosimetry was estimated on the basis of SPECT scans after injection of 925 MBq (25 mCi) 99mTc-EC-DG in seven patients with non-small-cell lung cancer (NSCLC) (19). The urinary bladder received the highest dose (0.0247 mGy/MBq (91 mrad/mCi)). Other organs that received high doses were the kidney (0.0123 mGy/MBq (45.6 mrad/mCi)) and lung (0.0056 mGy/MBq (20.7 mrad/mCi)). The effective dose equivalent was 0.0059 mSv/MBq (21.8 mrem/mCi). The blood clearance of 99mTc-EC-DG was rapid with <0.0005% ID at 1 h after injection. The primary lung tumor was visualized in six of the seven patients. The other patient was found to have granuloma, which was detected with [18F]FDG. The tumor/blood ratios were 4.0 and 20.5 for 99mTc-EC-DG and [18F]FDG, respectively.

NIH Support

CA16672

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.
Gurfinkel M., Ke S., Wen X., Li C., Sevick-Muraca E.M. Near-infrared fluorescence optical imaging and tomography. Dis Markers. 2003;19(2-3):107–21. [PMC free article: PMC3851384] [PubMed: 15096708]
5.
Tung C.H. Fluorescent peptide probes for in vivo diagnostic imaging. Biopolymers. 2004;76(5):391–403. [PubMed: 15389488]
6.
Smith T.A. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57(2):170–8. [PubMed: 10912295]
7.
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]
8.
Avril N. GLUT1 expression in tissue and (18)F-FDG uptake. J Nucl Med. 2004;45(6):930–2. [PubMed: 15181126]
9.
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]
10.
Fowler J.S., Ido T. Initial and subsequent approach for the synthesis of 18FDG. Semin Nucl Med. 2002;32(1):6–12. [PubMed: 11839070]
11.
Phelps M.E. PET: the merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41(4):661–81. [PubMed: 10768568]
12.
Phelps M.E., Mazziotta J.C. Positron emission tomography: human brain function and biochemistry. Science. 1985;228(4701):799–809. [PubMed: 2860723]
13.
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]
14.
Rohren E.M., Turkington T.G., Coleman R.E. Clinical applications of PET in oncology. Radiology. 2004;231(2):305–32. [PubMed: 15044750]
15.
Sokoloff L. Basic principles in imaging of regional cerebral metabolic rates. Res Publ Assoc Res Nerv Ment Dis. 1985;63:21–49. [PubMed: 2992057]
16.
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]
17.
Yang D.J., Kim C.G., Schechter N.R., Azhdarinia A., Yu D.F., Oh C.S., Bryant J.L., Won J.J., Kim E.E., Podoloff D.A. Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents. Radiology. 2003;226(2):465–73. [PubMed: 12563141]
18.
Yang D., Yukihiro M., Yu D.F., Ito M., Oh C.S., Kohanim S., Azhdarinia A., Kim C.G., Bryant J., Kim E.E., Podoloff D. Assessment of therapeutic tumor response using 99mtc-ethylenedicysteine-glucosamine. Cancer Biother Radiopharm. 2004;19(4):443–56. [PubMed: 15453959]
19.
Schechter, N.R., W.D. Erwin, D.J. Yang, E.E. Kim, R.F. Munden, K. Forster, L.C. Taing, J.D. Cox, H.A. Macapinlac, and D.A. Podoloff, Radiation dosimetry and biodistribution of (99m)Tc-ethylene dicysteine-deoxyglucose in patients with non-small-cell lung cancer. Eur J Nucl Med Mol Imaging, 2009. [PMC free article: PMC2758190] [PubMed: 19396440]
PubReader format: click here to try

Views

Search MICAD

Limit my Search:


Related information

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...