Influx rate of 18 F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts

Eur J Nucl Med Mol Imaging. 2019 Sep;46(10):2190-2198. doi: 10.1007/s00259-019-04375-8. Epub 2019 Jul 1.

Abstract

Purpose: 18F-fluoroaminosuberic acid (18F-FASu) is a recently developed amino acid tracer for positron emission tomography (PET) of oxidative stress that may offer improved tumour assessment over the conventional tracer 18F-fluorodeoxyglucose (18F-FDG). Our aim was to evaluate and relate dynamic 18F-FASu and 18F-FDG uptake with pharmacokinetic modelling to transporter protein expression levels in a panel of diverse tumour xenograft lines.

Methods: Four different tumour xenograft lines were implanted in female athymic nude mice: MAS98.12 and HBCx3 (breast), TPMX (osteosarcoma) and A549 (lung). Dynamic PET over 60 min was performed on a small animal unit. The time-activity curves (TACs) for 18F-FASu and 18F-FDG in individual tumours were used to extract early (SUVE; 2 min p.i.) and late (SUVL; 55 min p.i.) standardised uptake values. Pharmacokinetic two-tissue compartment models were applied to the TACs to estimate rate constants K1-k4 and blood volume fraction vB. Relative levels of cystine/glutamate antiporter subunit xCT were assessed by western blotting, and expression of GLUT1 and CD31 by immunohistochemistry.

Results: 18F-FASu showed higher SUVE, whilst 18F-FDG exhibited higher SUVL. Influx rate K1 for 18F-FASu was significantly correlated with xCT levels (p = 0.001) and was significantly higher than K1 for 18F-FDG (p < 0.001). K1 for 18F-FDG was significantly correlated with GLUT1 levels (p = 0.002). vB estimated from 18F-FASu and 18F-FDG TACs was highly consistent and significantly correlated (r = 0.85, p < 0.001). Two qualitatively different 18F-FASu uptake profiles were identified: type α with low xCT expression and low K1 (A549 and HBCx3), and type β with high xCT expression and high K1 (MAS98.12 and TPMX).

Conclusion: The influx rate of 18F-FASu reflects xCT activity in tumour xenografts. Dynamic PET with pharmacokinetic modelling is needed to fully appraise 18F-FASu distribution routes.

Keywords: 18F-FDG; 18F-fluoroaminosuberic acid; Cancer; Dynamic PET; Mouse model; Oxidative stress; Pharmacokinetic modelling; System XC −; Xenograft; xCT.

MeSH terms

  • A549 Cells
  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism*
  • Amino Acids, Dicarboxylic / pharmacokinetics*
  • Animals
  • Female
  • Fluorodeoxyglucose F18 / pharmacokinetics
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Mammary Neoplasms, Experimental / diagnostic imaging*
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Mice, Nude
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Positron-Emission Tomography
  • Protein Binding
  • Radiopharmaceuticals / pharmacokinetics*

Substances

  • 5-fluoroaminosuberic acid
  • Amino Acid Transport System y+
  • Amino Acids, Dicarboxylic
  • Glucose Transporter Type 1
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Radiopharmaceuticals
  • Slc2a1 protein, mouse
  • Slc7a11 protein, mouse
  • Fluorodeoxyglucose F18