This paper describes a novel series of 18F-labeled polyethyleneglycol (PEG)-stilbene derivatives as potential beta-amyloid (Abeta) plaque-specific imaging agents for positron emission tomography (PET). In these series of compounds, 18F 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 18F-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 [18F]fluoride giving the target compounds [18F]12a-d (EOS, specific activity, 900-1500 Ci/mmol; radiochemical purity >99%). In vivo biodistribution of these novel (18)F 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 [18F]12a-d confirmed the specific binding related to the presence of Abeta plaques. In addition, in vivo plaque labeling can be clearly demonstrated with these 18F-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 Abeta plaque imaging agents for studying patients with Alzheimer's disease.