[18F]α/γ-Fluorobenzylamine-folate

[18F]α/γ-FBA-folate

Leung K.

Publication Details

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In vitro Rodents

Background

[PubMed]

Folic acid 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 68/67/66Ga-DF-folate) have been studied in tumor imaging (4-7). Bettio et al. (8) reported a synthesis of 18F-labeled folate by a reaction of [18F]4-fluorobenzylamine (FBA) with the α- and γ-carboxyl groups of folic acid. [18F]α/γ-FBA-folate is being developed as a positron emission tomography (PET) agent for detection of folate receptors in vivo.

Synthesis

[PubMed]

Bettio et al. (8) coupled folic acid with [18F]FBA to yield a 4:1 mixture of [18F]γ-FBA-folate and

[18F]α-FBA-folate with radiochemical yields of 15-44% and specificity activity up to 24 GBq/μmol (0.65 Ci/μmol). [18F]FBA was prepared by a two-step reaction by standard nucleophilic radiofluorination of 4-cyano-N,N,-trimethylanilinium trifluoromethane sulfonate to form 4-[18F]-benzonitrile and reduction of the nitrile functional group by LiAlH4 to the amino functionality with radiochemical yields of 8-13%.

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 (8). The mean IC50 values for α-FBA-folate, γ-FBA-folate and folate were 71 ± 8, 62 ± 6 and 41 nM, respectively. Therefore, the α- and γ-FBA-folate have comparable binding affinity to that of native folic acid.

Animal Studies

Rodents

[PubMed]

Bettio et al. (8) performed biodistribution studies of [18F]α/γ-FBA-folate in nude mice bearing the KB-31 tumor xenografts. The organ with the highest accumulation was the kidneys (40.65%ID/g), followed by the tumor (6.65%ID/g), duodenum (5.01%ID/g), and liver (2.37%ID/g) at 125 min after [18F]α/γ-FBA-folate injection. Very high radioactivity was found in bile, urine, and faces. Pretreatment with folic acid (200 μg/mouse) reduced [18F]α/γ-FBA-folate accumulation by 80% in the tumor and 97% in the kidneys.

The whole body distribution of [18F]α/γ-FBA-folate was also assessed by PET imaging from 75 to 120 min after injection. The highest activity concentrations were visualized in the gallbladder, urinary bladder, and parts of the intestines. Moderate accumulation was observed in the kidneys, tumors, and liver. The accumulation of [18F]α/γ-FBA-folate was heterogeneous within the tumor, with higher radioactivity in the tumor rim. The accumulation of [18F]α/γ-FBA-folate in the tumor and kidneys was completely blocked by folic acid pretreatment.

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.

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]