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

Abstract

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. 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 (SUV_E; 2 min p.i.) and late (SUV_L; 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 v_B. Relative levels of cystine/glutamate antiporter subunit xCT were assessed by western blotting, and expression of GLUT1 and CD31 by immunohistochemistry. ¹⁸F-FASu showed higher SUV_E, whilst ¹⁸F-FDG exhibited higher SUV_L. 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). v_B 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). 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.