Masanao Aoki1, Tadashi Watabe2,3, Shushi Nagamori4,5, Sadahiro Naka6, Hayato Ikeda1, Pornparn Kongpracha4,5, Genki Horitsugi1, Yasukazu Kanai7,8, Eku Shimosegawa1,7,8, Yoshikatsu Kanai4, Jun Hatazawa1,7,9. 1. Department of Nuclear Medicine and Tracer Kinetics, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. 2. Department of Nuclear Medicine and Tracer Kinetics, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. watabe@tracer.med.osaka-u.ac.jp. 3. Medical Imaging Center for Translational Research, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. watabe@tracer.med.osaka-u.ac.jp. 4. Department of Bio-System Pharmacology, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. 5. Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. 6. Osaka University Hospital, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. 7. Medical Imaging Center for Translational Research, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. 8. Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. 9. Immunology Frontier Research Center, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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.
OBJECTIVE:L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of humancancer 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:Rattumor 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.