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Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2

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Abstract

Objective

L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of human cancer cells, while being minimally expressed in normal or inflammatory tissues. Therefore, LAT1-targeting PET tracers have been developed for cancer-specific imaging. The purpose of this study was to study the distribution of two LAT1-targeting PET tracers, L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) and L-3-18F-alpha-methyl tyrosine (18F-FAMT), in relation to the tumor blood flow, using rat xenograft models.

Methods

Rat tumor xenograft models of C6 glioma (n = 4; tumors = 8) and MIA PaCa-2 (pancreatic cancer) (n = 4; tumors = 6) were used. The expressions of LAT1 and CD98hc were evaluated by both immunofluorescence staining and western blot analysis. Dynamic PET was performed after injection of 18F-FAMT or 18F-FBPA (scan duration = 70 min) following 15O-water PET (scan duration = 10 min). The PET data were subjected to kinetic analyses, and the K1, k2, and total distribution volume (Vt) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their Vt. Tumor blood flow (TBF) was represented by the K1 value in 15O-water PET.

Results

LAT1/CD98hc expression was confirmed in both xenografts by immunofluorescence staining. Western blot analysis showed higher functional expression of LAT1 in the C6 glioma cells as compared to the MIA PaCa-2 cells (C6 glioma/MIA PaCa-2 relative expression ratio = 1.70). The Vt values of both 18F-FBPA and 18F-FAMT were significantly higher in the C6 glioma xenografts than in the MIA PaCa-2 xenografts (C6 glioma: 2.27 ± 0.35 and 2.03 ± 0.23, respectively; MIA PaCa-2: 1.28 ± 0.26 and 1.35 ± 0.15, respectively). Meanwhile, there was no significant correlation of the Vt value of either 18F-FBPA or 18F-FAMT with the TBF, in either the C6 glioma or the MIA PaCa-2 xenografts.

Conclusions

This study revealed that total distribution volumes of the LAT1-targeting PET tracers 18F-FBPA and 18F-FAMT were independent of the tumor blood flow and might reflect the functional expression levels of LAT1 in the C6 glioma and MIA PaCa-2 xenograft models.

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Acknowledgements

M.A. received support from the Osaka University Medical Doctor Scientist Training Program. We would like to thank all the members of the PET Drug Synthesis Department at Osaka University Hospital for preparing the tracers, the Department of Bio-system Pharmacology for providing support for the immunofluorescence staining, the Medical Imaging Center for Translational Research for their excellent technical assistance, and the Department of Nuclear Medicine and Tracer Kinetics for providing support for the experiments. This study was supported by the KAKENHI Grant-in-Aid for Scientific Research (S) (Number 24229008) and the KAKENHI (A) (Number 24249077) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. The authors have no potential conflict of interest to disclose in relation to this article.

Funding

This study was funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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Authors and Affiliations

  1. Department of Nuclear Medicine and Tracer Kinetics, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Masanao Aoki, Tadashi Watabe, Hayato Ikeda, Genki Horitsugi, Eku Shimosegawa & Jun Hatazawa

  2. Medical Imaging Center for Translational Research, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Tadashi Watabe, Yasukazu Kanai, Eku Shimosegawa & Jun Hatazawa

  3. Department of Bio-System Pharmacology, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shushi Nagamori, Pornparn Kongpracha & Yoshikatsu Kanai

  4. Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Shushi Nagamori & Pornparn Kongpracha

  5. Osaka University Hospital, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Sadahiro Naka

  6. Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yasukazu Kanai & Eku Shimosegawa

  7. Immunology Frontier Research Center, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Jun Hatazawa

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  1. Masanao Aoki
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Aoki, M., Watabe, T., Nagamori, S. 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 33, 394–403 (2019). https://doi.org/10.1007/s12149-019-01346-9

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