Background

[PubMed]

The phosphorylation of glucose, an initial and important step in cellular metabolism, is catalyzed by hexokinases (HKs) (1). There are four HKs in mammalian tissues. HKI, HKII, and HKIII have molecular weights of approximately 100,000 each. HKI is found mainly in the brain. HKII is insulin sensitive and 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 (2), which was detected in tumors from patients with lung, gastrointestinal, and breast cancer. The HKs, by converting glucose to glucose-6-phosphate, help to maintain the downhill gradient that results in the transport of glucose into cells through the facilitative glucose transporters (GLUT1-13) (3). GLUT4 and HKII are the major transporter and HK isoform 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 (2DG) was first developed to inhibit glucose utilization by cancer cells (4). HKs phosphorylate 2DG 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 (5). 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 stays intracellularly 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 alternations in glucose metabolism in brain, cancer, cardiovascular diseases, Alzheimer’s disease and other central nervous system disorders, and infectious, autoimmune, and inflammatory diseases (6-11).

Synthesis

[PubMed]

[¹⁸F]FDG was synthesized by a direct electrophilic fluorination of 3,4,6-tri-O-acetyl-d-glucal with [¹⁸F]F₂ gas with a radiochemical yield of 8% (12). [¹⁸F]FDG was also prepared by reacting ¹⁸F-labeled acetyl hypofluorite, prepared by reaction of ¹⁸F-labeled molecular fluorine with sodium acetate in glacial acetic acid, and tri-acetyl-d-glucal at room temperature. Overall radiochemical yield was about 24% with a radiochemical purity of 98%. The specific activity of [¹⁸F]FDG was about 25 GBq/mmol (685 mCi/mmol). The synthesis time was approximately 60 min (13). Subsequently, the radiochemical yields of [¹⁸F]FDG were improved to 50-60% by using various methods involving nucleophilic fluorination using fluoride of high specific activity (14-17). An automated synthesis of [¹⁸F]FDG using tetrabutylammonium [¹⁸F]fluoride was reported to give a radiochemical yield of 12-17% with 96-99% radiochemical purity (18).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

FDG and other glucose analogs were investigated as anticancer agents by inhibiting glycolysis of tumor cells grown in cell cultures. In vitro uptake studies of [¹⁸F]FDG by endothelial cells, monocytes, macrophages, neutrophils, granulocytes, lymphocytes, and tumor cells have been reported and shed some light on [¹⁸F]FDG uptake mechanisms in these cells (19-23). On the other hand, in organs such as the liver, FDG is taken up and rapidly released because of dephosphorylation by FDG-6-phosphatase (24). Therefore, the overall FDG uptake into cells is dependent on the activity of glucose transporters, HKs, and phosphatases.

Uptake of [¹⁸F]FDG in isolated human monocytes-macrophages (HMMs) in vitro was compared with that in human glioblastoma and pancreatic carcinoma cells (25). HMMs were cultured for 0, 7, and 14 days. [¹⁸F]FDG uptake in HMMs significantly increased with culture duration as monocytes differentiated into mature macrophages. The uptake of day 14 macrophages was similar to the two cancer cell lines. Lipopolysaccharide stimulation further enhanced [¹⁸F]FDG uptake in HMMs. [¹⁸F]FDG uptake significantly decreased with increasing glucose concentration in the medium. Radio-thin layer chromatography of intracellular metabolites revealed that [¹⁸F]FDG was trapped by HMMs mainly as [¹⁸F]FDG-6-phosphate and [¹⁸F]FDG-1,6-diphosphate. HMMs in tumors and inflamed tissues could result in high uptake of [¹⁸F]FDG.

Animal Studies

Human Studies

[PubMed]

In 1976, the first images of [¹⁸F]FDG metabolism in humans were obtained and showed the high uptake in the bladder, heart, and brain (5, 32). Regional kinetic constants and rCMRglc in normal human subjects were determined by [¹⁸F]FDG PET (33-36). Human dosimetry [PubMed] was estimated from absorbed dose in organs after intravenous administration of [¹⁸F]FDG using whole-body PET scans in six normal volunteers (37). The bladder received the highest dose of radioactivity, followed by the spleen, heart, and brain. Mejia et al (38) estimated the effective dose equivalent to be 0.024 mSv/MBq (81 mrem/mCi).

[¹⁸F]FDG PET imaging techniques are widely used in clinical applications. In central nervous system disorders [PubMed], the clinical applications are in Alzheimer’s disease, dementia, epilepsy, brain trauma, Huntington disease, cerebrovascular disorders, brain tumors, Schizophrenia, and mood disorders (39, 40). In oncology [PubMed], the clinical applications are in diagnosis, treatment monitoring, and tumor staging have been used in non-small cell lung cancer, colorectal carcinoma, malignant melanoma, Hodgkin and non-Hodgkin lymphoma, esophageal carcinoma, head and neck cancer, breast cancer, and thyroid carcinoma (9, 41). In cardiovascular disorders [PubMed], the clinical applications are in myocardial viability and atherosclerosis (42). In infectious and inflammatory diseases [PubMed], the clinical applications are in orthopedic infections, osteomyelitis, ileitis, sarcoidosis, rheumatologic disease, and vasculitis (42).

References

1.

Smith T.A. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57(2):170–8. [PubMed: 10912295]

2.

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]

3.

Avril N. GLUT1 expression in tissue and (18)F-FDG uptake. J Nucl Med. 2004;45(6):930–2. [PubMed: 15181126]

4.

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]

5.

Fowler J.S., Ido T. Initial and subsequent approach for the synthesis of 18FDG. Semin Nucl Med. 2002;32(1):6–12. [PubMed: 11839070]

6.

Phelps M.E. PET: the merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41(4):661–81. [PubMed: 10768568]

7.

Phelps M.E., Mazziotta J.C. Positron emission tomography: human brain function and biochemistry. Science. 1985;228(4701):799–809. [PubMed: 2860723]

8.

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]

9.

Rohren E.M., Turkington T.G., Coleman R.E. Clinical applications of PET in oncology. Radiology. 2004;231(2):305–32. [PubMed: 15044750]

10.

Sokoloff L. Basic principles in imaging of regional cerebral metabolic rates. Res Publ Assoc Res Nerv Ment Dis. 1985;63:21–49. [PubMed: 2992057]

11.

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]

12.

Reivich M., Kuhl D., Wolf A., Greenberg J., Phelps M., Ido T., Casella V., Fowler J., Gallagher B., Hoffman E., Alavi A., Sokoloff L. Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose. Acta Neurol Scand Suppl. 1977;64:190–1. [PubMed: 268783]

13.

Diksic M., Jolly D. New high-yield synthesis of 18F-labelled 2-deoxy-2-fluoro-D-glucose. Int J Appl Radiat Isot. 1983;34(6):893–6. [PubMed: 6874115]

14.

Mock B.H., Vavrek M.T., Mulholland G.K. Back-to-back "one-pot" [18F]FDG syntheses in a single Siemens-CTI chemistry process control unit. Nucl Med Biol. 1996;23(4):497–501. [PubMed: 8832706]

15.

Taylor M.D., Roberts A.D., Nickles R.J. Improving the yield of 2-[18F]fluoro-2-deoxyglucose using a microwave cavity. Nucl Med Biol. 1996;23(5):605–9. [PubMed: 9044687]

16.

Toorongian S.A., Mulholland G.K., Jewett D.M., Bachelor M.A., Kilbourn M.R. Routine production of 2-deoxy-2-[18F]fluoro-D-glucose by direct nucleophilic exchange on a quaternary 4-aminopyridinium resin. Int J Rad Appl Instrum B. 1990;17(3):273–9. [PubMed: 2341282]

17.

Hamacher K., Coenen H.H., Stocklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986;27(2):235–8. [PubMed: 3712040]

18.

Brodack J.W., Dence C.S., Kilbourn M.R., Welch M.J. Robotic production of 2-deoxy-2-[18F]fluoro-D-glucose: a routine method of synthesis using tetrabutylammonium [18F]fluoride. Int J Rad Appl Instrum [A] 1988;39(7):699–703. [PubMed: 2844702]

19.

Deichen J.T., Schmidt C., Prante O., Maschauer S., Papadopoulos T., Kuwert T. Influence of TSH on uptake of [18F]fluorodeoxyglucose in human thyroid cells in vitro. Eur J Nucl Med Mol Imaging. 2004;31(4):507–12. [PubMed: 14722674]

20.

Smith T.A. The rate-limiting step for tumor [18F]fluoro-2-deoxy-D-glucose (FDG) incorporation. Nucl Med Biol. 2001;28(1):1–4. [PubMed: 11182558]

21.

Maschauer S., Prante O., Hoffmann M., Deichen J.T., Kuwert T. Characterization of 18F-FDG uptake in human endothelial cells in vitro. J Nucl Med. 2004;45(3):455–60. [PubMed: 15001687]

22.

Osman S., Danpure H.J. The use of 2-[18F]fluoro-2-deoxy-D-glucose as a potential in vitro agent for labelling human granulocytes for clinical studies by positron emission tomography. Int J Rad Appl Instrum B. 1992;19(2):183–90. [PubMed: 1601671]

23.

Vinals F., Gross A., Testar X., Palacin M., Rosen P., Zorzano A. High glucose concentrations inhibit glucose phosphorylation, but not glucose transport, in human endothelial cells. Biochim Biophys Acta. 1999;1450(2):119–29. [PubMed: 10354504]

24.

Caraco C., Aloj L., Chen L.Y., Chou J.Y., Eckelman W.C. Cellular release of [18F]2-fluoro-2-deoxyglucose as a function of the glucose-6-phosphatase enzyme system. J Biol Chem. 2000;275(24):18489–94. [PubMed: 10764804]

25.

Deichen J.T., Prante O., Gack M., Schmiedehausen K., Kuwert T. Uptake of [18F]fluorodeoxyglucose in human monocyte-macrophages in vitro. Eur J Nucl Med Mol Imaging. 2003;30(2):267–73. [PubMed: 12552345]

26.

Gallagher B.M., Ansari A., Atkins H., Casella V., Christman D.R., Fowler J.S., Ido T., MacGregor R.R., Som P., Wan C.N., Wolf A.P., Kuhl D.E., Reivich M. Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals. J Nucl Med. 1977;18(10):990–6. [PubMed: 903484]

27.

Fukuda H., Matsuzawa T., Abe Y., Endo S., Yamada K., Kubota K., Hatazawa J., Sato T., Ito M., Takahashi T., Iwata R., Ido T. Experimental study for cancer diagnosis with positron-labeled fluorinated glucose analogs: [18F]-2-fluoro-2-deoxy-D-mannose: a new tracer for cancer detection. Eur J Nucl Med. 1982;7(7):294–7. [PubMed: 6981508]

28.

van Waarde A., Cobben D.C., Suurmeijer A.J., Maas B., Vaalburg W., de Vries E.F., Jager P.L., Hoekstra H.J., Elsinga P.H. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004;45(4):695–700. [PubMed: 15073267]

29.

Som P., Atkins H.L., Bandoypadhyay D., Fowler J.S., MacGregor R.R., Matsui K., Oster Z.H., Sacker D.F., Shiue C.Y., Turner H., Wan C.N., Wolf A.P., Zabinski S.V. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med. 1980;21(7):670–5. [PubMed: 7391842]

30.

Noda A., Ohba H., Kakiuchi T., Futatsubashi M., Tsukada H., Nishimura S. Age-related changes in cerebral blood flow and glucose metabolism in conscious rhesus monkeys. Brain Res. 2002;936(1-2):76–81. [PubMed: 11988232]

31.

Scharko A.M., Perlman S.B., Hinds P.W.n., Hanson J.M., Uno H., Pauza C.D. Whole body positron emission tomography imaging of simian immunodeficiency virus-infected rhesus macaques. Proc Natl Acad Sci U S A. 1996;93(13):6425–30. [PMC free article: PMC39039] [PubMed: 8692831]

32.

Reivich M., Kuhl D., Wolf A., Greenberg J., Phelps M., Ido T., Casella V., Fowler J., Hoffman E., Alavi A., Som P., Sokoloff L. The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res. 1979;44(1):127–37. [PubMed: 363301]

33.

Hawkins R.A., Mazziotta J.C., Phelps M.E., Huang S.C., Kuhl D.E., Carson R.E., Metter E.J., Riege W.H. Cerebral glucose metabolism as a function of age in man: influence of the rate constants in the fluorodeoxyglucose method. J Cereb Blood Flow Metab. 1983;3(2):250–3. [PubMed: 6841472]

34.

Heiss W.D., Pawlik G., Herholz K., Wagner R., Goldner H., Wienhard K. Regional kinetic constants and cerebral metabolic rate for glucose in normal human volunteers determined by dynamic positron emission tomography of [18F]-2-fluoro-2-deoxy-D-glucose. J Cereb Blood Flow Metab. 1984;4(2):212–23. [PubMed: 6609929]

35.

Huang S.C., Phelps M.E., Hoffman E.J., Sideris K., Selin C.J., Kuhl D.E. Noninvasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol. 1980;238(1):E69–82. [PubMed: 6965568]

36.

Phelps M.E., Huang S.C., Hoffman E.J., Selin C., Sokoloff L., Kuhl D.E. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol. 1979;6(5):371–88. [PubMed: 117743]

37.

Jones S.C., Alavi A., Christman D., Montanez I., Wolf A.P., Reivich M. The radiation dosimetry of 2 [F-18]fluoro-2-deoxy-D-glucose in man. J Nucl Med. 1982;23(7):613–7. [PubMed: 6979616]

38.

Mejia A.A., Nakamura T., Masatoshi I., Hatazawa J., Masaki M., Watanuki S. Estimation of absorbed doses in humans due to intravenous administration of fluorine-18-fluorodeoxyglucose in PET studies. J Nucl Med. 1991;32(4):699–706. [PubMed: 2013810]

39.

Newberg A., Alavi A., Reivich M. Determination of regional cerebral function with FDG-PET imaging in neuropsychiatric disorders. Semin Nucl Med. 2002;32(1):13–34. [PubMed: 11839066]

40.

Tai Y.F., Piccini P. Applications of positron emission tomography (PET) in neurology. J Neurol Neurosurg Psychiatry. 2004;75(5):669–76. [PMC free article: PMC1763584] [PubMed: 15090557]

41.

Otsuka H., Graham M., Kubo A., Nishitani H. Clinical utility of FDG PET. J Med Invest. 2004;51(1-2):14–9. [PubMed: 15000251]

42.

Alavi A., Kung J.W., Zhuang H. Implications of PET based molecular imaging on the current and future practice of medicine. Semin Nucl Med. 2004;34(1):56–69. [PubMed: 14735459]