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Synthesis and preliminary biological evaluation of O-2((2-[18F]fluoroethyl)methylamino)ethyltyrosine ([18F]FEMAET) as a potential cationic amino acid PET tracer for tumor imaging

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Abstract

Amino acid transport is an attractive target for oncologic imaging. Despite a high demand of cancer cells for cationic amino acids, their potential as PET probes remains unexplored. Arginine, in particular, is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Cationic amino acids are transported by several cationic transport systems including, ATB0,+ (SLC6A14), which is upregulated in certain human cancers including cervical, colorectal and estrogen receptor-positive breast cancer. In this work, we report the synthesis and preliminary biological evaluation of a new cationic analog of the clinically used PET tumor imaging agent O-(2-[18F]fluroethyl)-l-tyrosine ([18F]FET), namely O-2((2-[18F]fluoroethyl)methylamino)ethyltyrosine ([18F]FEMAET). Reference compound and precursor were prepared by multi-step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [18F]fluorination in 16–20 % decay-corrected yields with radiochemical purity >99 %. The new tracer showed good stability in vitro and in vivo. Cell uptake assays demonstrated that FEMAET and [18F]FEMAET accumulate in prostate cancer (PC-3) and small cell lung cancer cells (NCI-H69), with an energy-dependent mechanism. Small animal PET imaging with NCI-H69 xenograft-bearing mice revealed good tumor visualization comparable to [18F]FET and low brain uptake, indicating negligible transport across the blood–brain barrier. In conclusion, the non-natural cationic amino acid PET probe [18F]FEMAET accumulates in cancer cells in vitro and in vivo with possible involvement of ATB0,+.

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Abbreviations

[18F]FDG:

2-[18F]fluoro-2-deoxy-d-glucose

mTOR:

Mammalian target of rapamycin

LAT1:

System L amino acid transporter

[18F]FET:

O-(2-[18F]fluroethyl)-l-tyrosine

CAT:

Cationic amino acid transporter family

NO:

Nitric oxide

[18F]AFETP:

(S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid

[18F]FEMAET:

O-2((2-[18F]fluoroethyl)methylamino)ethyltyrosine

DEAD:

Diethyl azodicarboxylate

KCN:

Potassium cyanide

DIPEA:

Diisopropylethylamine

DAST:

Diethylaminosulfurtrifluoride

CBr4 :

Carbon tetrabromide

PPh3 :

Triphenylphosphine

[18F]FDOPA:

l-3,4-Dihydroxy-6-[18F]fluorophenylalanine

EBSS:

EARLE balanced salt solution

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Acknowledgments

We thank Claudia Keller for the excellent technical help in conducting in vitro and in vivo experiments.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Zurich, Switzerland

    Aristeidis Chiotellis, Adrienne Müller, Karin Weyermann, Dominique S. Leutwiler, Roger Schibli, Simon M. Ametamey & Stefanie D. Krämer

  2. Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, University Hospital, Zurich, Switzerland

    Dominique S. Leutwiler & Linjing Mu

Authors
  1. Aristeidis Chiotellis
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  2. Adrienne Müller
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  3. Karin Weyermann
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  4. Dominique S. Leutwiler
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  5. Roger Schibli
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  6. Simon M. Ametamey
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  7. Stefanie D. Krämer
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  8. Linjing Mu
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Correspondence to Linjing Mu.

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Chiotellis, A., Müller, A., Weyermann, K. et al. Synthesis and preliminary biological evaluation of O-2((2-[18F]fluoroethyl)methylamino)ethyltyrosine ([18F]FEMAET) as a potential cationic amino acid PET tracer for tumor imaging. Amino Acids 46, 1947–1959 (2014). https://doi.org/10.1007/s00726-014-1754-7

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  • DOI: https://doi.org/10.1007/s00726-014-1754-7

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