Synthesis, in Vitro Evaluation, and Radiolabelling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis
Journal of Medicinal Chemistry
American Chemical Society
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Betts, H., Milicevic Sephton, S., Tong, C., Awais, R., Hill, P., Perkins, A., & Aigbirhio, F. (2016). Synthesis, in Vitro Evaluation, and Radiolabelling 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
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.
H.M.B. acknowledges the Royal Society of Chemistry Research Fund for partial funding of this project and the NIHR Clinical Research Network (East Midlands) for funding her post. We are grateful to the U.K. Medical Research Council (MRC) for funding (Grant G9219778). C.T. was supported by the MRC/University of Nottingham Doctoral Training Program. S.M.S. acknowledges the EPSRC Mass Spectrometry Facility for funding her attendance at the Mass Spectrometry Summer School 2016. Dr. W. Chan (University of Nottingham) is acknowledged for access to synthetic chemistry facilities. The EPSRC Mass Spectrometry Facility at the University of Swansea is acknowledged for performing HRMS analyses.
MEDICAL RESEARCH COUNCIL (MR/M009041/1)
MEDICAL RESEARCH COUNCIL (MR/M024873/1)
External DOI: https://doi.org/10.1021/acs.jmedchem.6b00968
This record's URL: https://www.repository.cam.ac.uk/handle/1810/261461