Synthesis, in Vitro Evaluation, and Radiolabeling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis.
There is currently no ideal radiotracer for imaging of protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18-labeled 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 radiolabeled 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 the fluoroethyl analogue 7b as a lead compound. The fluorine-18 analogue was prepared via nucleophilic substitution of the corresponding tosylate precursor in a modest radiochemical yield of 2 ± 0.6% with excellent radiochemical purity (>99%) and showed complete stability over 3 h at ambient temperature.
Nottingham University Hospitals NHS Trust, PET/CT Center, Nottingham City Hospital , Hucknall Road, Nottingham NG5 1PB, U.K.
Helen M
HM
Betts
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Center, University of Cambridge , Box 65 Cambridge Biomedical Campus, Cambridge CB2 0QQ, U.K.
Selena
S
Milicevic Sephton
School of Life Sciences, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
Carmen
C
Tong
Radiological Sciences, School of Medicine, University of Nottingham, Queen's Medical Center , Derby Road, Nottingham NG7 2UH, U.K.
Ramla O
RO
Awais
School of Biosciences, University of Nottingham , Sutton Bonington Campus, Sutton Bonington LE12 5RD, U.K.
Philip J
PJ
Hill
Radiological Sciences, School of Medicine, University of Nottingham, Queen's Medical Center , Derby Road, Nottingham NG7 2UH, U.K.
Alan C
AC
Perkins
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Center, University of Cambridge , Box 65 Cambridge Biomedical Campus, Cambridge CB2 0QQ, U.K.
Franklin I
FI
Aigbirhio
D001426:Bacterial Proteins / Q000032:analysis* / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D007553:Isotope Labeling; D008163:Luminescent Measurements; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D014176:Protein Biosynthesis; D011691:Puromycin / Q000031:analogs & derivatives* / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D011868:Radioisotopes / Q000737:chemistry; D013211:Staphylococcus aureus / Q000378:metabolism; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D011868:Radioisotopes; D011691:Puromycin