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Synthesis, in vitro evaluation, and radiolabeling of fluorinated puromycin analogues: potential candidates for PET imaging of protein synthesis

Betts, Helen M.; Sephton, Selena Milicevic; Tong, Carmen; Awais, Ramla; Hill, Philip J.; Perkins, Alan C.; Aigbirhio, Franklin I.

Authors

Helen M. Betts

Selena Milicevic Sephton

Carmen Tong

Ramla Awais

PHIL HILL phil.hill@nottingham.ac.uk
Associate Professor

Alan C. Perkins

Franklin I. Aigbirhio



Abstract

There is currently no ideal radiotracer for imaging protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18 labelled amino acid-based radiotracers predominantly visualize amino acid transporter processes, and in many cases they are not incorporated into nascent proteins at all. Others are radiolabelled with the short half-life positron emitter carbon-11 which is rather impractical for many PET centers. Based on the puromycin (6) structural manifold, a series of 10 novel derivatives of 6 was prepared via Williamson ether synthesis from a common intermediate. A bioluminescence assay was employed to study their inhibitory action on protein synthesis which identified fluoroethyl analogue (7b) as a lead compound. The fluorine-18 analogue was prepared via nucleophilic substitution of the corresponding tosylate precursor in modest radiochemical yield 2±0.6% and excellent radiochemical purity (>99%) and showed complete stability over 3 h at ambient temperature.

Citation

Betts, H. M., Sephton, S. M., Tong, C., Awais, R., Hill, P. J., Perkins, A. C., & Aigbirhio, F. I. (2016). Synthesis, in vitro evaluation, and radiolabeling of fluorinated puromycin analogues: potential candidates for PET imaging of protein synthesis. Journal of Medicinal Chemistry, 59(20), 9422-9430. https://doi.org/10.1021/acs.jmedchem.6b00968

Journal Article Type Article
Acceptance Date Oct 3, 2016
Online Publication Date Oct 3, 2016
Publication Date Oct 3, 2016
Deposit Date Dec 19, 2016
Publicly Available Date Dec 19, 2016
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 59
Issue 20
Pages 9422-9430
DOI https://doi.org/10.1021/acs.jmedchem.6b00968
Keywords Positron emission tomography; protein synthesis; puromycin; fluorine-18
Public URL http://eprints.nottingham.ac.uk/id/eprint/39443
Publisher URL http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00968
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
Additional Information This is the author's version of a submitted work that was subsequently accepted for publication in the Journal of Medicinal Chemistry, c2016 American Chemical Society under the title Synthesis, in Vitro Evaluation, and Radiolabeling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00968

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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