Advertisement

Preclinical evaluation of an 18F-trifluoroborate methionine derivative for glioma imaging

  • Xiangyu Yang
  • Zhibo Liu
  • Huimin Zhang
  • Zhu Li
  • Jeeva P. Munasinghe
  • Gang Niu
  • Gaojun Teng
  • Xiaoyuan Chen
Original Article

Abstract

Purpose

11C–methionine (MET) is one of the most commonly used amino acid tracers for PET imaging of brain tumors. In this study, we report an 18F-labeled boron-derived methionine analogue, denoted as 18F-B-MET, as a potential substitute of 11C–MET for glioma PET imaging.

Methods

19F-B-MET was synthesized from readily available chemicals according to our previous publication. For kit development, 19F-B-MET was aliquoted in quantities of 10 nmol for on-demand one-step labeling. The 18F-labeling was performed by 18F-19F isotope exchange, and quality control was performed by both HPLC and radio-TLC. Uptake of the tracer was determined in GL26, C6 and U87 tumor cells. PET imaging and the biodistribution assay were performed on mice bearing subcutaneous or orthotopic C6 and U87 tumor xenografts.

Results

Starting with 740–1110 MBq 18F-fluoride, >370 MBq of 18F-B-MET was obtained in 25 min (n = 5) with >99% purity and high specific activity (>37 GBq/μmol). 18F-B-MET demonstrated excellent in vitro stability with <1% decomposition after incubation with plasma for 2 h. In vitro cell uptake assay showed that 18F-B-MET accumulated in tumor cells in a time dependent manner and could be competitively inhibited by natural methionine and other L-type transporter transported amino acids. In vivo biodistribution and imaging studies showed high tumor accumulation (2.99 ± 0.23 %ID/g, n = 6) compared with low uptake of brain (0.262 ± 0.05 %ID/g, n = 6) at 60 min after injection in a subcutaneous C6 tumor model. Orthotropic C6 and U87 tumors were clearly visualized with high tumor to brain ratios at 60 min post-injection, corroborating with tumor L-type amino acid transporter 1 (LAT-1) expression levels.

Conclusion

18F-B-MET was radiolabeled with high yield in a one-step labeling process, showed excellent pharmacokinetic properties in vivo, with high tumor-to-brain contrast.

Keywords

Positron emission tomography Methionine Tumor imaging LAT-1 18F-B-MET One-step 18F-labeling 

Notes

Funding

This work was supported by the National Basic Research Program of China (973 program, 2013CB733803, and 2013CB733802) and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Chung JK, Kim YK, Kim SK, Lee YJ, Paek S, Yeo JS, et al. Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Eur J Nucl Med Mol Imaging. 2002;29:176–82.CrossRefPubMedGoogle Scholar
  2. 2.
    Lindholm P, Leskinen S, Nagren K, Lehikoinen P, Ruotsalainen U, Teras M, et al. Carbon-11-methionine PET imaging of malignant melanoma. J Nucl Med. 1995;36:1806–10.PubMedGoogle Scholar
  3. 3.
    Ashkenazy H, Erez E, Martz E, Pupko T, Ben-Tal N. ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res. 2010;38:W529–33.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pei J, Kim BH, Grishin NV. PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic Acids Res. 2008;36:2295–300.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wang J, Chen X, Su L, Li P, Liu B, Zhu Z. LAT-1 functions as a promotor in gastric cancer associated with clinicopathologic features. Biomed Pharmacother. 2013;67:693–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Yanagisawa N, Hana K, Nakada N, Ichinoe M, Koizumi W, Endou H, et al. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas. Cancer Med. 2014;3:1246–55.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci. 2012;103:382–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Lin J, Raoof DA, Thomas DG, Greenson JK, Giordano TJ, Robinson GS, et al. L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma. Neoplasia. 2004;6:74–84.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Detta A, Cruickshank GS. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors. Cancer Res. 2009;69:2126–32.CrossRefPubMedGoogle Scholar
  10. 10.
    Imai H, Kaira K, Oriuchi N, Yanagitani N, Sunaga N, Ishizuka T, et al. L-type amino acid transporter 1 expression is a prognostic marker in patients with surgically resected stage I non-small cell lung cancer. Histopathology. 2009;54:804–13.CrossRefPubMedGoogle Scholar
  11. 11.
    Betsunoh H, Fukuda T, Anzai N, Nishihara D, Mizuno T, Yuki H, et al. Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma. BMC Cancer. 2013;13:509.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lindholm P, Leskinen S, Lapela M. Carbon-11-methionine uptake in squamous cell head and neck cancer. J Nucl Med. 1998;39:1393–7.PubMedGoogle Scholar
  13. 13.
    Miyazawa H, Arai T, Iio M, Hara T. PET imaging of non-small-cell lung carcinoma with carbon-11-methionine: relationship between radioactivity uptake and flow-cytometric parameters. J Nucl Med. 1993;34:1886–91.PubMedGoogle Scholar
  14. 14.
    Kanegae K, Nakano I, Kimura K, Kaji H, Kuge Y, Shiga T, et al. Comparison of MET-PET and FDG-PET for differentiation between benign lesions and lung cancer in pneumoconiosis. Ann Nucl Med. 2007;21:331–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Dankerl A, Liebisch P, Glatting G, Friesen C, Blumstein NM, Kocot D, et al. Multiple myeloma: molecular imaging with 11C-Methionine PET/CT--initial experience. Radiology. 2007;242:498–508.CrossRefPubMedGoogle Scholar
  16. 16.
    Gulyas B, Halldin C. New PET radiopharmaceuticals beyond FDG for brain tumor imaging. Q J Nucl Med Mol Imaging. 2012;56:173–90.PubMedGoogle Scholar
  17. 17.
    Glaudemans AW, Enting RH, Heesters MA, Dierckx RA, van Rheenen RW, Walenkamp AM, et al. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur J Nucl Med Mol Imaging. 2013;40:615–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Kawai N, Kagawa M, Hatakeyama T, Tamiya T, Noshiyama Y, Yamamoto Y, et al. 11C-methionine positron emission tomography in brain tumor. No Shinkei Geka. 2008;36:847–59.PubMedGoogle Scholar
  19. 19.
    Ullrich RT, Kracht L, Brunn A, Herholz K, Frommolt P, Miletic H, et al. Methyl-L-11C-methionine PET as a diagnostic marker for malignant progression in patients with glioma. J Nucl Med. 2009;50:1962–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Terakawa Y, Tsuyuguchi N, Iwai Y, Yamanaka K, Higashiyama S, Takami T, et al. Diagnostic accuracy of 11C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med. 2008;49:694–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Laforest R, Liu X. Image quality with non-standard nuclides in PET. Q J Nucl Med Mol Imaging. 2008;52:151–8.PubMedGoogle Scholar
  22. 22.
    Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, et al. Boramino acid as a marker for amino acid transporters. Sci Adv. 2015;1:e1500694.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kim CS, Cho SH, Chun HS, Lee SY, Endou H, Kanai Y, et al. BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells. Biol Pharm Bull. 2008;31:1096–100.CrossRefPubMedGoogle Scholar
  24. 24.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  25. 25.
    Coenen HH, Kling P, Stocklin G. Cerebral metabolism of L-[2-18F]fluorotyrosine, a new PET tracer of protein synthesis. J Nucl Med. 1989;30:1367–72.PubMedGoogle Scholar
  26. 26.
    Inoue T, Tomiyoshi K, Higuichi T, Ahmed K, Sarwar M, Aoyagi K, et al. Biodistribution studies on L-3-[fluorine-18]fluoro-alpha-methyl tyrosine: a potential tumor-detecting agent. J Nucl Med. 1998;39:663–7.PubMedGoogle Scholar
  27. 27.
    Shoup TM, Olson J, Hoffman JM, Votaw J, Eshima D, Eshima L, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med. 1999;40:331–8.PubMedGoogle Scholar
  28. 28.
    Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med. 1999;40:205–12.PubMedGoogle Scholar
  29. 29.
    Ploessl K, Wang L, Lieberman BP, Qu W, Kung HF. Comparative evaluation of 18F-labeled glutamic acid and glutamine as tumor metabolic imaging agents. J Nucl Med. 2012;53:1616–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang L, Lieberman BP, Ploessl K, Kung HF. Synthesis and evaluation of (1)(8)F labeled FET prodrugs for tumor imaging. Nucl Med Biol. 2014;41:58–67.CrossRefPubMedGoogle Scholar
  31. 31.
    Halsted CH, Medici V. Vitamin-dependent methionine metabolism and alcoholic liver disease. Adv Nutr. 2011;2:421–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2017

Authors and Affiliations

  • Xiangyu Yang
    • 1
    • 2
  • Zhibo Liu
    • 2
  • Huimin Zhang
    • 2
  • Zhu Li
    • 2
  • Jeeva P. Munasinghe
    • 3
  • Gang Niu
    • 2
  • Gaojun Teng
    • 1
    • 4
  • Xiaoyuan Chen
    • 2
    • 5
  1. 1.Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda HospitalMedical School of Southeast UniversityNanjingChina
  2. 2.Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and BioengineeringNational Institutes of Health (NIH)BethesdaUSA
  3. 3.Mouse Imaging Facility, National Institute of Neurological Disorders and StrokeNIHBethesdaUSA
  4. 4.NanjingChina
  5. 5.BethesdaUSA

Personalised recommendations