18F-labeled styrylpyridines as PET agents for amyloid plaque imaging

Positron emission tomography (PET) imaging of beta-amyloid (A beta) 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 A beta plaques in the brain. We have successfully reported a series of F-18-labeled fluoropegylated stilbenes for PET imaging studies. Encouraging results clearly demonstrated the usefulness of 18F-labeled stilbenes as potential A beta 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 (K-i =2.5 +/- 0.4 nM, with [I-125]IMPY as radioligand). No-carrier-added [F-18]2 was successfully prepared by [F-18]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 [F-18]2 showed adequate lipophilicity (log P=3.22). In vivo biodistribution of [F-18]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 A beta-plaque-specific brain imaging agents. Autoradiography of AD brain sections and homogenate binding with postmortem AD brain tissues confirmed the high binding signal of [F-18]2 due to the presence of A beta plaques. These prelin-linary results suggest that novel PET tracers may be potentially useful for the imaging of A beta plaques in the living human brain. (c) 2007 Published by Elsevier Inc.