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.