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Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer

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Abstract

Purpose

The imaging potential of a new 18F-labelled methionine derivative, S-(3-[18F]fluoropropyl)-d-homocysteine (18F-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts.

Methods

Expression of members of the system L (LAT isoforms 1–4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of 18F-D-FPHCys were in vitro uptake studies by comparing it with [1-14C]-l-methionine (14C-MET) and in vivo by PET imaging. In addition, the specific involvement of LAT1 transporters in 18F-D-FPHCys accumulation was tested by silencing LAT1 mRNA transcription with siRNAs. To determine the proliferative activity in tumour xenografts ex vivo, Ki-67 staining was used as a biomarker.

Results

A431 cells showed the highest 18F-D-FPHCys uptake in vitro and in vivo followed by Colo 205, PC3 and HT-29. A similar pattern of retention was observed with 14C-MET. 18F-D-FPHCys retention was strongly correlated with LAT1 expression both in vitro (R 2 = 0.85) and in vivo (R 2 = 0.99). Downregulation of LAT1 by siRNA inhibited 18F-D-FPHCys uptake, demonstrating a clear dependence on this transporter for tumour uptake. Furthermore, 18F-D-FPHCys accumulation mirrored cellular proliferation.

Conclusion

The favourable properties of 18F-D-FPHCys make this tracer a promising imaging probe for detection of tumours as well as for the noninvasive evaluation and monitoring of tumour growth.

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Acknowledgments

We gratefully acknowledge Susan Jackson, Rachael Walker, Kerry Ardley and Jeannette Valentan for technical assistance. This study was funded by the Australian Government Cooperative Research Centre for Biomedical Imaging Development Ltd. (CRCBID), Bundoora, Victoria, Australia.

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Authors and Affiliations

  1. Molecular Imaging and Targeted Therapeutics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia

    Delphine Denoyer, Laura Kirby, Peter Roselt, Oliver C. Neels & Rodney J. Hicks

  2. Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Delphine Denoyer, Laura Kirby, Kelly Waldeck & Rodney J. Hicks

  3. Department PET and Nuclear Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    Thomas Bourdier

  4. ANSTO LifeSciences, Australian Nuclear Science and Technology Organisation, Sydney, New South Wales, Australia

    Rachael Shepherd & Andrew Katsifis

  5. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia

    Rodney J. Hicks

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  1. Delphine Denoyer
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Correspondence to Delphine Denoyer.

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Financial support

This study was funded by the Australian Government Cooperative Research Centre for Biomedical Imaging Development Ltd (CRCBID), Bundoora, Victoria, Australia.

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Denoyer, D., Kirby, L., Waldeck, K. et al. Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer. Eur J Nucl Med Mol Imaging 39, 703–712 (2012). https://doi.org/10.1007/s00259-011-2017-4

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  • DOI: https://doi.org/10.1007/s00259-011-2017-4

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