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Eur J Nucl Med Mol Imaging. 2019 Jul 1. doi: 10.1007/s00259-019-04375-8. [Epub ahead of print]

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

Author information

1
Department of Physics, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway.
2
Department of Medical Physics, Oslo University Hospital, Oslo, Norway.
3
Department of Chemistry, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway.
4
Department of Tumour Biology, Oslo University Hospital, Oslo, Norway.
5
Department of Radiation Biology, Oslo University Hospital, Oslo, Norway.
6
Department of Physics, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway. eirik.malinen@fys.uio.no.
7
Department of Medical Physics, Oslo University Hospital, Oslo, Norway. eirik.malinen@fys.uio.no.

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

PMID:
31264167
DOI:
10.1007/s00259-019-04375-8

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