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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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[18F]6-fluoro-3-O-methyl-L-3,4-dihydroxyphenylalanine

[18F]OMFD
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894, vog.hin.mln.ibcn@dacim

Created: ; Last Update: January 8, 2008.

Chemical name:[18F]6-fluoro-3-O-methyl-L-3,4-dihydroxyphenylalanineimage 46488333 in the ncbi pubchem database
Abbreviated name:[18F]OMFD
Synonym:3-O-methyl-6-[18F]-fluoro-L-DOPA
Agent Category:Compound
Target:L amino acid transporters (LAT)
Target Category:Binding
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-Primate Mammals
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Although 18F-fluorodeoxyglucose (18F-FDG) is considered the gold standard for the detection of tumors using positron emission tomography (PET), the use of this agent as a tumor diagnostic agent has a limitation (1, 2): the uptake of 18F-FDG by cells is based on the glucose transport system. An increased glucose metabolism is a characteristic feature of cancer cells, so this feature can be used to distinguish the neoplastic from normal cells. However, because the uptake of 18F-FDG is nonspecific, use of this agent does not distinguish between cells that are cancerous and those that take up 18F-FDG because of other etiologies such as inflammation, infection, or even brown fat or granulomas, etc (2). Also, slow-growing malignant tissues (such as prostate tumors) might not show an increased glucose metabolism and thus can not be detected with 18F-FDG (3). As a consequence, many other radiolabeled ligands, such as amino acids or their derivatives, have been developed and used for the detection and diagnosis of malignant tumors (1).

In this regard, methionine labeled with radioactive carbon (as 11C) has been developed and extensively evaluated for the detection of neoplastic lesions. However, because the label has a short half-life, several 18F amino acid analogs have been generated and studied for the diagnosis of neoplastic lesions with PET (4). An increased uptake of amino acids that correlated with upregulation of the amino acid transport system in proliferating cells was observed, and this resulted in a high tumor/normal tissue ratio regardless of the cell cycle phase (4, 5). In the pursuit of developing agents for the detection of cancers, investigators have evaluated a phenylalanine derivative, 3-O-methyl-6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18F-OMFD), for tumor imaging (6, 7). 18F-OMFD was shown to be taken up by neoplastic cells and has been suggested to be suitable for the detection of squamous cell head and neck carcinoma by imaging (8).

Synthesis

[PubMed]

The synthesis of 18F-OMFD has been detailed by Fϋchtner and Steinbach (9). Briefly, a precursor of 18F-OMFD, N-formyl-3-O-methyl-4-O-ditert-butyldicarbonate-6-trimethyl-stannyl-L-dihydroxyphenylalanine-ethyl ester was derived from N-formyl-3,4-O-ditert-butyldicarbonate-6-trimethylstannyl-L-dihydroxyphenylalanine-ethyl ester as described by Namavari et al. (10). The precursor was dissolved in trichlorofluoromethane at room temperature and reacted with gaseous 18F-fluorine while the temperature was decreased to -20oC. Subsequently, 12 M hydrochloric acid was added to the reaction mixture and the temperature was increased to 70oC. Excess solvent was evaporated by blowing gaseous nitrogen through the mixture. The reaction vessel was then closed, and a partial hydrolysis of the products was allowed to proceed at 130oC for 10 min at an elevated pressure. Subsequently, 18F-OMFD was separated from the reaction mixture by high-performance liquid chromatography on a C-8 column. The total time taken for preparation at the end of bombardment was 50 min with a yield of 20–25% (decay corrected, as related to 18F-fluorine). The radiochemical purity of 18F-OMFD was >98% with a specific activity of ~20 GBq/mmol (540 mCi/mmol) in ~50 preparations (9).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro uptake of 18F-OMFD was investigated in HT-29 (of human colon adenocarcinoma origin), FaDu (of squamous cell carcinoma origin), and RBE4 (of rat brain origin) cell lines in the presence or absence of a competitive transport inhibitor such as 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid and α-(methylamino)isobutyric acid plus serine and with or without sodium (6). The transport of 18F-OMFD was shown to be mediated primarily through a high-capacity, sodium-independent, amino acid transport system, and the FaDu cells showed the highest uptake.

Animal Studies

Rodents

[PubMed]

Using PET, Haase et al. investigated the uptake of 18F-OMFD in mice bearing FaDu or HT-29 cell xenograft tumors (8). Maximum radioactivity was observed to accumulate in the tumors and the pancreas in both tumor models. The uptake was higher in the FaDu tumors with a standardized uptake value (SUV) of 3.07 ± 0.66 compared to 1.19 ± 0.26 for the HT-29 cell tumors. From this study the investigators concluded that 18F-OMFD could be used for the detection of poorly differentiated, squamous cell tumors in the head and neck (8).

Other Non-Primate Mammals

[PubMed]

The transport of 18F-OMFD and 18F-dihydroxyphenylalanine (18F-DOPA) across the blood–brain barrier (BBB) was investigated with PET in pigs of different ages (11). The transport rate of both neutral amino acids across the BBB was observed to decrease as the brains of the animals developed, but the cerebral blood flow and the plasma concentrations of these amino acids did not change during brain development. The transport of 18F-OMFD and 18F-DOPA was mediated primarily by the L amino acid transporter 1. Data from the study indicated that developmental changes of the transporter system for neutral amino acids in these animals after birth lead to a decrease in the BBB permeability for these amino acids during brain development.

Non-Human Primates

[PubMed]

No references are currently available

Human Studies

[PubMed]

The use of 18F-OMFD for brain tumor imaging and whole-body biodistribution was studied using PET in humans (7). With this technique, 16 of 19 studied patients were suspected to have viable brain tumors with a standardized uptake value of 3.0 ± 0.8 and a tumor/non-tumor ratio of 1.9 ± 0.5. Maximum uptake of the label was observed between 15 and 30 min after administration with a subsequent slow decrease in uptake. The label did not accumulate in any specific organ and was eliminated through the urinary system (7). The investigators caution that, although 18F-OMFD appears to be a suitable agent to image brain tumors, because it has been evaluated in only a small number of patients it remains to be demonstrated that it is as specific as O-(2-[18F]fluoroethyl)-L-tyrosine to differentiate between a tumor and inflammation or as promising as 3-[18F]fluoro-L-α-methyl-tyrosine to image malignant tumors (7).

In another study, the use of 18F-OMFD was compared to that of 18F-FDG and 18F-DOPA for the diagnosis of metastatic medullary thyroid carcinoma (MTC) (12). With results from this study the investigators concluded that, although 18F-FDG and 18F-DOPA could detect highly suspicious foci, suggesting local recurrence or metastasis of MTC, the foci were not detected with 18F-OMFD.

Supplemental Information

[Disclaimers]

References

1.
Chen W. Clinical applications of PET in brain tumors. J Nucl Med. 2007;48(9):1468–81. [PubMed: 17704239]
2.
Groves A.M., Win T., Haim S.B., Ell P.J. Non-[18F]FDG PET in clinical oncology. Lancet Oncol. 2007;8(9):822–30. [PubMed: 17765191]
3.
Kayani I., Groves A.M. 18F-fluorodeoxyglucose PET/CT in cancer imaging. Clin Med. 2006;6(3):240–4. [PubMed: 16826854]
4.
Jager P.L., Vaalburg W., Pruim J., de Vries E.G., Langen K.J., Piers D.A. Radiolabeled amino acids: basic aspects and clinical applications in oncology. J Nucl Med. 2001;42(3):432–45. [PubMed: 11337520]
5.
Sasajima T., Miyagawa T., Oku T., Gelovani J.G., Finn R., Blasberg R. Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines. Eur J Nucl Med Mol Imaging. 2004;31(9):1244–56. [PubMed: 15141325]
6.
Bergmann R., Pietzsch J., Fuechtner F., Pawelke B., Beuthien-Baumann B., Johannsen B., Kotzerke J. 3-O-methyl-6-18F-fluoro-L-dopa, a new tumor imaging agent: investigation of transport mechanism in vitro. J Nucl Med. 2004;45(12):2116–22. [PubMed: 15585490]
7.
Beuthien-Baumann B., Bredow J., Burchert W., Fuchtner F., Bergmann R., Alheit H.D., Reiss G., Hliscs R., Steinmeier R., Franke W.G., Johannsen B., Kotzerke J. 3-O-methyl-6-[18F]fluoro-L-DOPA and its evaluation in brain tumour imaging. Eur J Nucl Med Mol Imaging. 2003;30(7):1004–8. [PubMed: 12768333]
8.
Haase C., Bergmann R., Fuechtner F., Hoepping A., Pietzsch J. L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo. J Nucl Med. 2007;48(12):2063–71. [PubMed: 18056335]
9.
Fuchtner F., Steinbach J. Efficient synthesis of the 18F-labelled 3-O-methyl-6-[18F]fluoro-L-DOPA. Appl Radiat Isot. 2003;58(5):575–8. [PubMed: 12735974]
10.
Namavari M., Bishop A., Satyamurthy N., Bida G., Barrio J.R. Regioselective radiofluorodestannylation with [18F]F2 and [18F]CH3COOF: a high yield synthesis of 6-[18F]Fluoro-L-dopa. Int J Rad Appl Instrum [A] 1992;43(8):989–96. [PubMed: 1330984]
11.
Brust P., Vorwieger G., Walter B., Fuchtner F., Stark H., Kuwabara H., Herzau M., Opfermann T., Steinbach J., Ganapathy V., Bauer R. The influx of neutral amino acids into the porcine brain during development: a positron emission tomography study. Brain Res Dev Brain Res. 2004;152(2):241–53. [PubMed: 15351512]
12.
Beuthien-Baumann B., Strumpf A., Zessin J., Bredow J., Kotzerke J. Diagnostic impact of PET with 18F-FDG, 18F-DOPA and 3-O-methyl-6-[18F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2007;34(10):1604–9. [PubMed: 17435996]
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