Background

[PubMed]

In a variety of solid tumors, hypoxia was found to lead to tumor progression and the resistance of tumors to chemotherapy and radiotherapy (1-3). Tumor oxygenation is heterogeneously distributed within human tumors (4). Hypoxia in malignant tumors is thought to be a major factor limiting the efficacy of chemotherapy and radiotherapy. It would be beneficial to assess tumor oxygenation before and after therapy to provide an evaluation of tumor response to treatment and an insight into new therapeutic treatments (5). Tumor oxygenation is measured invasively using computerized polarographic oxygen-sensitive electrodes, which is regarded as the gold standard (6). Functional and non-invasive imaging of intra-tumoral hypoxia has been demonstrated to be feasible for the measurement of tumor oxygenation (7). This has led to the search and development of hypoxia-targeted, non-invasive markers of tumor hypoxia.

Chapman proposed the use of 2-nitroimidazoles for hypoxia imaging (8). 2-Nitroimidazole compounds are postulated to undergo reduction in hypoxic condition, forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (9). [¹⁸F]Fluoromisonidazole ([¹⁸F]FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia (7). However, it has slow clearance kinetics and a high lipophilicity, resulting in substantially high background in PET scan. Novel 2-nitroimidazoles, such as [¹⁸F]FETA, [¹⁸F]FETNIM, 4-Br[¹⁸F]FPN, [¹⁸F]EF1, and [¹⁸F]EF5, are currently being investigated as potential markers of tumor hypoxia [PubMed]. 2-(2-Nitroimidazol-1H-yl)-N-(3,3,3-trifluoropropyl)acetamide (EF3) is a 3-trifluorinated analog of EF1 (2-(2-nitro-1H-imidazol-1-yl)-N-(3-fluoropropyl)acetamide). EF3 binding to hypoxic tumor cells was shown to be dependent on oxygen and less dependent on the intracellular level of reductase system (10, 11). [¹⁸F]EF3 is being evaluated as a PET probe for detection of tumor hypoxia.

Synthesis

[PubMed]

Josse et al. (12) reported that [¹⁸F]EF3 was synthesized by coupling 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate with [¹⁸F]-3,3,3-trifluoropropylamine in 5% radiochemical yield. [¹⁸F]-3,3,3-trifluoropropylamine was obtained with 40% overall chemical yield by oxidative [¹⁸F]-fluorodesulfurization of ethyl N-phthalimido-3-aminopropane dithioate, followed by deprotection with hydrazine. The total synthesis time was <90 min from the [¹⁸F]HF production in the cyclotron to the purification of [¹⁸F]EF3, which had a specific activity of 2.6 GBq/mmol (71 mCi/mmol) with a radiochemical purity >95%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No publication is currently available.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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References

1.

Serkies K. , Jassem J. Chemotherapy in the primary treatment of cervical carcinoma. Crit Rev Oncol Hematol. 2005; 54 (3):197–208. [PubMed: 15890269]

2.

Vaupel P. , Mayer A. Hypoxia and anemia: effects on tumor biology and treatment resistance. Transfus Clin Biol. 2005; 12 (1):5–10. [PubMed: 15814285]

3.

Rajendran J.G. , Krohn K.A. Imaging hypoxia and angiogenesis in tumors. Radiol Clin North Am. 2005; 43 (1):169–87. [PubMed: 15693655]

4.

Vaupel P. , Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Suppl 5Oncologist. 2004; 9 :4–9. [PubMed: 15591417]

5.

Dehdashti F. , Grigsby P.W. , Mintun M.A. , Lewis J.S. , Siegel B.A. , Welch M.J. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003; 55 (5):1233–8. [PubMed: 12654432]

6.

Raleigh J.A. , Dewhirst M.W. , Thrall D.E. Measuring Tumor Hypoxia. Semin Radiat Oncol. 1996; 6 (1):37–45. [PubMed: 10717160]

7.

Foo S.S. , Abbott D.F. , Lawrentschuk N. , Scott A.M. Functional imaging of intratumoral hypoxia. Mol Imaging Biol. 2004; 6 (5):291–305. [PubMed: 15380739]

8.

Chapman J.D. Hypoxic sensitizers--implications for radiation therapy. N Engl J Med. 1979; 301 (26):1429–32. [PubMed: 229413]

9.

Chapman J.D. , Baer K. , Lee J. Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res. 1983; 43 (4):1523–8. [PubMed: 6831401]

10.

Cobb L.M. , Nolan J. , Hacker T. Retention of misonidazole in normal and malignant tissues: interplay of hypoxia and reductases. Int J Radiat Oncol Biol Phys. 1992; 22 (4):655–9. [PubMed: 1544833]

11.

Franko A.J. , Koch C.J. , Garrecht B.M. , Sharplin J. , Hughes D. Oxygen dependence of binding of misonidazole to rodent and human tumors in vitro. Cancer Res. 1987; 47 (20):5367–76. [PubMed: 3652041]

12.

Josse O. , Labar D. , Georges B. , Gregoire V. , Marchand-Brynaert J. Synthesis of [18F]-labeled EF3 [2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide], a marker for PET detection of hypoxia. Bioorg Med Chem. 2001; 9 (3):665–75. [PubMed: 11310602]

13.

Mahy P. , De Bast M. , Leveque P.H. , Gillart J. , Labar D. , Marchand J. , Gregoire V. Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3. Eur J Nucl Med Mol Imaging. 2004; 31 (9):1263–72. [PubMed: 15197503]

14.

Mahy P. , De Bast M. , Gillart J. , Labar D. , Gregoire V. Detection of tumour hypoxia: comparison between EF5 adducts and [18F]EF3 uptake on an individual mouse tumour basis. Eur J Nucl Med Mol Imaging. 2006; 33 (5):553–6. [PubMed: 16523307]