F-18 polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain

This paper describes a novel series of F-18-labeled polyethyleneglycol (PEG)-stilbene derivatives as potential P-amyloid (A beta) plaque-pecific imaging agents for positron emission tomography (PET). In these series of compounds, F-18 is linked to the stilbene through a PEG chain, of which the number of ethoxy groups ranges from 2 to 5. The purpose of adding PEG groups is to lower the lipophilicity and improve bioavailability. The syntheses of the cold compounds and the F-18-labeled PEG stilbene derivatives are successfully achieved. All of the fluorinated stilbenes displayed high binding affinities in an assay using postmortem AD brain homogenates (K-i=2.9-6.7 nM). Labeling was successfully performed by a substitution of the mesylate group of 10a-d by [F-18]fluoride giving the target compounds [F-18]12a-d (EOS, specific activity, 900-1500 Ci/mmol; radiochemical purity >99%). In vivo biodistribution of these novel F-18 ligands in normal mice exhibited excellent brain penetrations and rapid washouts after an intravenous injection (6.6-8.1 and 1.2-2.6 %dose/g at 2 and 60 min, respectively). Autoradiography of postmortem AD brain sections of [F-18]12a-d confirmed the specific binding related to the presence of A beta plaques. In addition, in vivo plaque labeling can be clearly demonstrated with these F-18-labeled agents in transgenic mice (Tg2576), a useful animal model for Alzheimer's disease. In conclusion, the preliminary results strongly suggest these fluorinated PEG stilbene derivatives are suitable candidates as A plaque imaging agents for studying patients with Alzheimer's disease. (c) 2005 Published by Elsevier Inc.