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 Jun;33(6):394-403. doi: 10.1007/s12149-019-01346-9. Epub 2019 Feb 28.

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.

Keywords: C6 glioma; LAT1; MIA PaCa-2; Small-animal PET; Tumoral blood flow.

MeSH terms

  • Animals
  • Blood Circulation*
  • Boron Compounds / metabolism
  • Boron Compounds / pharmacokinetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • Glioma / blood supply
  • Glioma / diagnostic imaging
  • Glioma / metabolism
  • Glioma / pathology*
  • Humans
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Male
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / diagnostic imaging
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / metabolism
  • Phenylalanine / pharmacokinetics
  • Positron-Emission Tomography*
  • Radioactive Tracers
  • Radiopharmaceuticals / metabolism
  • Radiopharmaceuticals / pharmacokinetics*
  • Rats
  • Tissue Distribution
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Tyrosine / pharmacokinetics

Substances

  • Boron Compounds
  • Large Neutral Amino Acid-Transporter 1
  • Radioactive Tracers
  • Radiopharmaceuticals
  • 4-borono-2-fluorophenylalanine
  • 2-fluoro-alpha-methyltyrosine
  • Tyrosine
  • Phenylalanine