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.

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: https://nottingham-repository.worktribe.com/output/824920
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00968
• 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
• Contract Date: Dec 19, 2016