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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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66/67/68Ga-γ-Deferoxamine-folate

66/67/68Ga-γ-DF-folate
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: January 30, 2011.

Chemical name:66/67/68Ga-γ-Deferoxamine-folateimage 14709924 in the ncbi pubchem database
Abbreviated name:66/67/68Ga-γ-DF-folate
Synonym:
Agent category:Folic acid (folate)
Target:Putative folate receptor
Target category:Receptor
Method of detection:Positron emission tomography (PET); single photon emission computed tomography (SPECT)
Source of signal:66/67/68Ga
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Folic acid (folate) is a water-soluble B vitamin (1) that is essential for methylation and DNA synthesis. The primary pathway for entry of folate into cells is through the facilitated transporter, which has a low affinity for folate (Michaelis constant (Km) = 1-5 μM). Some cells in the choroid plexus, kidney, lung, thyroid, spleen, placenta, and thymus also possess a higher affinity (dissociation constant (Kd) = 0.5 nM) receptor that allows folate uptake via receptor-mediated endocytosis. Some human epithelial tumor cells were found to overexpress folate-binding protein (2). More than 90% of human ovarian and endometrial cancers express the high-affinity receptor, which is absent in normal tissues. Breast, colorectal, renal, and lung carcinomas also overexpress the folate receptor but at lower frequencies (20-50%). Activated macrophages, but not resting macrophages, have been also found to have folate receptor (3).

Several folate-based conjugates (111In-DTPA-folate, 99mTc-EC-folate and [18F]FBA-folate) have been studied in tumor imaging (4-8). Deferoxamine (DF), a chelating agent, was conjugated to folic acid forming a mixture of two isomers, DF-α-folate and DF-γ-folate. Only the DF-γ-folate isomer was able to displace [3H]folic acid from its receptors with a similar IC50 to folic acid (2.5 versus 2.4 nM) (9). 68/67/66Ga-γ-DF-folate is being developed as an imaging agent for detection of folate receptors in vivo with either positron emission tomography (PET) or single photon emission computed tomography (SPECT).

Synthesis

[PubMed]

Wang et al. (9) coupled DF-γ-folate (2.25 μmol) with 118 MBq (3.2 mCi) 67GA-(acetylacetone)3 in buffered saline at room temperature for 24 h to yield 67Ga-γ-DF-folate with >98% radiochemical purity. Radiochemical yields exceeded 80%. Mathias et al. (5) reported that 66Ga-γ-DF-folate and 68Ga-γ-DF-folate were similarly radiolabeled at 50°C for 15-30 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The human nasopharyngeal carcinoma KB-31 cell line has putative folate receptors as determined by [3H]folate binding studies in cultures (9). The mean IC50 values for DF-γ-folate, and folate were 25 and 24 nM, respectively. Binding of 67Ga-γ-DF-folate to cells was rapid and reached a maximal binding of 18% and 32% at 4°C and 37°C in 30 min, respectively. Both bindings were inhibited by folic acid and DF-γ-folate but not by DF-α-folate. As controls, 67Ga-DF and 67Ga-citrate showed little binding to the cells.

Animal Studies

Rodents

[PubMed]

Mathias et al. (6, 10) performed biodistribution studies of 67Ga-γ-DF-folate in nude mice bearing the KB-31 tumor xenografts. The organ with the highest accumulation was the tumor (5.2%ID/g), followed by the kidneys (2.02%ID/g), and liver (0.46%ID/g) at 4 h after 67Ga-γ-DF-folate injection. Tumor/blood, tumor/muscle, tumor/liver and tumor/kidney ratio were 409, 124, 11, and 3, respectively. Pretreatment (5 min before the tracer) with folic acid (2.4 mg/mouse) reduced 67Ga-γ-DF-folate accumulation to 0.26%ID/g in the tumor. Administration of folate at 3.5 h after the tracer reduced the tumor accumulation to 2.22%ID/g at 4.5 h. 67Ga-DF showed no accumulation in the tumor.

The whole body distribution of 66Ga-γ-DF-folate (174 MBq or 4.7 mCi/mouse) was also assessed by PET imaging at 2.5 h after injection (5). The highest activity concentrations were visualized in the tumors and kidneys. The accumulation of 66Ga-γ-DF-folate in the tumors and kidneys was blocked by excess folic acid (0.9 mg/mouse) co-injection.

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.

NIH Support

R01 CA86307, R01-CA70845

References

1.
Stanger O. Physiology of folic acid in health and disease. Curr Drug Metab. 2002;3(2):211–23. [PubMed: 12003352]
2.
Ke C.Y., Mathias C.J., Green M.A. The folate receptor as a molecular target for tumor-selective radionuclide delivery. Nucl Med Biol. 2003;30(8):811–7. [PubMed: 14698784]
3.
Nakashima-Matsushita N., Homma T., Yu S., Matsuda T., Sunahara N., Nakamura T., Tsukano M., Ratnam M., Matsuyama T. Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum. 1999;42(8):1609–16. [PubMed: 10446858]
4.
Mathias C.J., Hubers D., Low P.S., Green M.A. Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical. Bioconjug Chem. 2000;11(2):253–7. [PubMed: 10725102]
5.
Mathias C.J., Lewis M.R., Reichert D.E., Laforest R., Sharp T.L., Lewis J.S., Yang Z.F., Waters D.J., Snyder P.W., Low P.S., Welch M.J., Green M.A. Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals. Nucl Med Biol. 2003;30(7):725–31. [PubMed: 14499330]
6.
Mathias C.J., Wang S., Low P.S., Waters D.J., Green M.A. Receptor-mediated targeting of 67Ga-deferoxamine-folate to folate-receptor-positive human KB tumor xenografts. Nucl Med Biol. 1999;26(1):23–5. [PubMed: 10096497]
7.
Mathias C.J., Wang S., Waters D.J., Turek J.J., Low P.S., Green M.A. Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. J Nucl Med. 1998;39(9):1579–85. [PubMed: 9744347]
8.
Bettio A., Honer M., Muller C., Bruhlmeier M., Muller U., Schibli R., Groehn V., Schubiger A.P., Ametamey S.M. Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive Tumors. J Nucl Med. 2006;47(7):1153–1160. [PubMed: 16818950]
9.
Wang S., Lee R.J., Mathias C.J., Green M.A., Low P.S. Synthesis, purification, and tumor cell uptake of 67Ga-deferoxamine--folate, a potential radiopharmaceutical for tumor imaging. Bioconjug Chem. 1996;7(1):56–62. [PubMed: 8741991]
10.
Mathias C.J., Wang S., Lee R.J., Waters D.J., Low P.S., Green M.A. Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate. J Nucl Med. 1996;37(6):1003–8. [PubMed: 8683292]
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