Positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain is a potentially valuable tool for studying the pathophysiology of Alzheimer's disease (AD). It may also be applicable for measuring the effectiveness of therapeutic drugs aimed at lowering Abeta plaques in the brain. We have successfully reported a series of 18F-labeled fluoropegylated stilbenes for PET imaging studies. Encouraging results clearly demonstrated the usefulness of 18F-labeled stilbenes as potential Abeta plaque-imaging agents. In the present study, we applied a similar approach to a styrylpyridine backbone structure. Among all derivatives examined, (E)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-5-(4-dimethylaminostyryl)-pyridine (2) displayed high binding affinity in postmortem AD brain homogenates (Ki=2.5+/-0.4 nM, with [125I]IMPY as radioligand). No-carrier-added [18F]2 was successfully prepared by [18F]fluoride displacement of the corresponding tosylate precursor with a high labeling yield (30-40%) and a high radiochemical purity (>99%). Specific activity at the end of synthesis was determined to be 1500-2000 Ci/mmol. The tracer [18F]2 showed adequate lipophilicity (log P=3.22). In vivo biodistribution of [18F]2 in normal mice exhibited excellent initial brain penetration and rapid washout (7.77% and 1.03% dose/g in the brain at 2 and 30 min after intravenous injection, respectively)--properties that are highly desirable for Abeta-plaque-specific brain imaging agents. Autoradiography of AD brain sections and homogenate binding with postmortem AD brain tissues confirmed the high binding signal of [18F]2 due to the presence of Abeta plaques. These preliminary results suggest that novel PET tracers may be potentially useful for the imaging of Abeta plaques in the living human brain.