Evaluation of D-isomer of 18F-FBPA for oncology PET focusing on the differentiation of glioma and inflammation

Document Type : Original Article

Authors

1 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan

2 Institute for Radiation Sciences, Osaka University, Osaka, Japan

3 Department of Bio-system Pharmacology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan

4 Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, Nara, Japan

5 Deparment of Radiology, Osaka University Hospital, Immunology Frontier Research Center, Osaka University, Osaka, Japan

6 Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan

7 Research Center for Nuclear Physics, Osaka University, Osaka, Japan

Abstract

Objective(s): L-4-borono-2-18F-fluoro-phenylalanine (L-[18F]FBPA), a substrate of L-type amino acid transporter 1 (LAT1), is a tumor-specific probe used in positron emission tomography (PET). On the other hand, it has not been examined whether another isomer D-[18F]FBPA accumulates specifically in the tumor. Here, we compared the accumulation of D-[18F]FBPA in C6 glioma and inflammation to evaluate the performance of D-[18F]FBPA as a tumor-specific probe.
Methods: HEK293-LAT1 and HEK293-LAT2 cells were tested for [14C]-leucine or [14C]-alanine transport, and IC50 values of L- and D-FBPA were evaluated in both cell types. PET was conducted in rat xenograft model of C6 glioma with LAT1 expression and model of turpentine oil-induced subcutaneous inflammation (n=10 for both models). The concentrations of D-[18F]FBPA were compared between glioma and inflammatory lesion using standardized uptake value (SUV).
Results: In contrast to L-FBPA, which inhibited substrate uptake in both HEK293-LAT1 and -LAT2 cells, D-FBPA showed no inhibitory effect on both cells, suggesting low transporter selectivity of D-[18F]FBPA against LAT1 and LAT2. Static PET analysis showed low accumulation of D-[18F]FBPA in C6 glioma and inflammatory lesion (SUVmax=0.80±0.16, 0.56±0.09, respectively). Although there was a statistical difference in SUVmax between these tissues, it was difficult to distinguish glioma from inflammation on the PET image due to its low uptake level. Therefore, it was suggested that D-[18F]FBPA is not a suitable tumor-specific probe for oncology PET in contrast to L-[18F]FBPA.
Conclusion: This study demonstrated that D-[18F]FBPA is not a LAT1-specific PET probe and shows low uptake in C6 glioma, indicating its unsuitability as a tumor diagnosis PET probe.

Keywords

References

  1. Ishiwata K, Ido T, Mejia AA, Ichihashi M, Mishima Y. Synthesis and radiation dosimetry of 4-borono-2-[18F]fluoro-D, L-phenylalanine: A target compound for PET and boron neutron capture therapy. Int J Rad Appl Instrum A. 1991; 42(4):325–8.
  2. Ishiwata K. 4-Borono-2- 18F-fluoro- L-phenylalanine PET for boron neutron capture therapy-oriented diagnosis : overview of a quarter century of research. Ann Nucl Med. 2019; 33(4):223–36.
  3. Watabe T, Ikeda H, Nagamori S, Wiriyasermkul P, Tanaka Y, Naka S, et al. 18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11C-Methionine PET. Eur J Nucl Med Mol Imaging. 2017; 44(2):321–31.
  4. Yanagida O, Kanai Y, Chairoungdua A, Kyung D. Human L-type amino acid transporter 1 ( LAT1 ): characterization of function and expression in tumor cell lines. Biochim Biophys Acta. 2001; 1514(2):291–302.
  5. Shimizu A, Kaira K, Kato M, Yasuda M, Takahashi A, Tominaga H, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma. Melanoma Res. 2015; 25(5):399–405.
  6. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter1 expression in resectable stage I – III nonsmall cell lung cancer. Br J Cancer. 2008; 742–8.
  7. Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, et al. Prognostic significance of amino-acid transporter expression ( LAT1 , ASCT2 , and xCT ) in surgically resected tongue cancer. Br J Cancer. 2014; 110(10):2506–13.
  8. Pineda M, Fernández E, Torrents D, Estévez R, López C, Camps M, et al. Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999; 274(28):19738–44.
  9. Wiriyasermkul P, Nagamori S, Tominaga H, Oriuchi N, Kaira K, Nakao H, et al. Transport of 3-fluoro-L-α-methyl-tyrosine by tumor-upregulated L-type amino acid transporter 1: A cause of the tumor uptake in PET. J Nucl Med. 2012; 53(8):1253–61.
  10. Tsukada H, Sato K, Fukumoto D, Nishiyama S, Harada N, Kaikuchi T. Evaluation of D-isomers of O-11C-Methyl tyrosine and O-18F-fluoromethyl tyrosine as tumor-imaging agents in tumor-bearing mice. J Nucl Med. 2006; 47(4):679–89.
  11. Ohshima Y, Hanaoka H, Tominaga H, Kanai Y. Biological evaluation of 3- [18F]fluoro-α-methyl- D-tyrosine ( D-[18F]FAMT) as a novel amino acid tracer for positron emission tomography. Ann Nucl Med. 2013; 27(4):314–24.
  12. Kanazawa M, Nishiyama S, Hashimoto F, Kakiuchi T, Tsukada H. Evaluation of D-isomers of 4-borono-2-18F-fluoro-phenylalanine and O- 11C-methyl-tyrosine as brain tumor imaging agents: a comparative PET study with their L-isomers in rat brain glioma. EJNMMI Res. 2018; 8(1):47.
  13. Khunweeraphong N, Nagamori S, Wiriyasermkul P, Nishinaka Y. Establishment of Stable Cell Lines With High Expression of Heterodimers of Human 4F2hc and Human Amino Acid Transporter LAT1 or LAT2 and Delineation of Their Differential Interaction With α -Alkyl Moieties. J Pharmacol Sci. 2012; 119(4):368–80.
  14. Bao Q, Newport D, Chen M, Stout DB, Chatziioannou AF. Performance Evaluation of the Inveon Dedicated PET Preclinical Tomograph Based on the NEMA NU-4 Standards. J Nucl Med. 2009; 50(3):401–8.
  15. Aoki M, Watabe T, Nagamori S, Naka S, Ikeda H, Kongpracha P, et al. Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2. Ann Nucl Med. 2019; 33(6):394–403.
  16. Modemann DJ, Zlatopolskiy BD, Urusova EA, Zischler J, Craig A, Ermert J, et al. 2-[18F] Fluorophenylalanine: Synthesis by Nucleophilic 18F-Fluorination and Preliminary Biological Evaluation. Synth. 2019; 51(3):664–76.
  17. Wongthai P, Hagiwara K, Miyoshi Y, Wiriyasermkul P, Wei L, Ohgaki R, et al. Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2. Cancer Sci. 2015; 106(3):279–86
Asia Oceania Journal of Nuclear Medicine and Biology
Volume 8, Issue 2
July 2020
Pages 102-108

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