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

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 (V_t) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their V_t. 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 V_t 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 V_t 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.

https://ift.tt/2GQeZuk