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Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review

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Abstract

Due to its metabolism via the serotonin and kynurenine pathways, tryptophan plays a key role in multiple disease processes including cancer. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative positron emission tomography (PET) radiotracers. While human studies with such tracers have been confined to C-11-labeled compounds, preclinical development of F-18-labeled tryptophan-based radiotracers has surged in recent years. We performed a systematic review of studies reporting on such F-18-labeled tryptophan tracers to summarize and compare their biological characteristics and their potential for tumor imaging, with a particular focus on key enzymes of the kynurenine pathway (indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]), which play an important role in tumoral immune resistance. From a PubMed search, English language articles including data on the preparation and radiochemical and/or biological characteristics of F-18-labeled tryptophan derivative radiotracers were reviewed. A total of 19 original papers included data on 15 unique radiotracers, the majority of which were synthesized with an adequate radiochemical yield. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer thus far. Biodistribution studies showed high uptake in the pancreas, while the L-type amino acid transporter was the dominant transport mechanism for most of the reviewed tracers. Tracers tested for tumor uptake showed accumulation in tumor cell lines in vitro and in xenografts in vivo, often with favorable tumor-to-background uptake ratios in comparison with clinically used F-18-labeled radiotracers. Five tracers showed promise for imaging IDO activity, including 1-(2-[18F]fluoroethyl)-L-tryptophan and a F-18-labeled analog of alpha-[11C]methyl-L-tryptophan tested clinically in previous studies. Two radiotracers were metabolized by TDO but showed defluorination in vivo. In summary, most F-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several reported tracers could be candidates for further testing and validation toward PET imaging applications in a variety of human diseases.

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Authors and Affiliations

  1. Department of Pediatrics, Wayne State University and PET Center and Translational Imaging Laboratory, Children’s Hospital of Michigan, 3901 Beaubien St., Detroit, MI, 48201, USA

    Flóra John, Otto Muzik & Csaba Juhász

  2. Department of Neurology, Wayne State University, 4201 St. Antoine St., Detroit, MI, 48201, USA

    Otto Muzik & Csaba Juhász

  3. Department of Neurosurgery, Wayne State University, 4201 St. Antoine St., Detroit, MI, 48201, USA

    Sandeep Mittal & Csaba Juhász

  4. Karmanos Cancer Institute, 4100 John R. St., Detroit, MI, 48201, USA

    Sandeep Mittal & Csaba Juhász

  5. Fralin Biomedical Research Institute, Virginia Tech Carilion School of Medicine, Roanoke, VA, 24014, USA

    Sandeep Mittal

  6. Virginia Tech School of Neuroscience, Blacksburg, VA, 24061, USA

    Sandeep Mittal

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  1. Flóra John
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John, F., Muzik, O., Mittal, S. et al. Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review. Mol Imaging Biol 22, 805–819 (2020). https://doi.org/10.1007/s11307-019-01430-6

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