(18)F-Labeled benzylideneaniline derivatives as new ligands for beta-amyloid plaque imaging in Alzheimer`s disease

Abstract

Introduction: Noninvasive early detection of beta-amyloid (A beta) plaques might be useful for the treatment of patients with Alzheimer`s disease (AD). We herein describe the synthesis of (18)F-labeled benzylideneaniline derivatives using a novel labeling approach for imaging A beta plaques in AD patients. Methods: Benzyldenaniline derivatives were synthesized by reacting fluorobenzaldehyde and corresponding aniline derivatives. Fluorobenzaldehyde was labeled with (18)F by incubating [(18)F]fluoride with N,N,N-trimethylbenzaldehyde in the presence of tetrabutylammonium bicarbonate. In vitro binding assay, stability test and biodistribution study were performed. Results: These compounds were stable at alkaline pH (pH > 9) however, they were hydrolyzed rapidly at physiological pH (pH similar to 7.4). The K(i) values of amine-containing benzylideneaniline derivatives for A beta(1-40) and A beta(1-42) aggregates were 26-78 nM. These (18)F-labeled benzylideneaniline derivatives showed high brain uptake and rapid clearance after intravenous administration in normal mice (1.8-3.1%ID/g at 2 min and 0.1-1.2%ID/g at 30 min). The low level of bone activity at 30 min indicated that these (18)F-labeled benzylideneanilines are not prone to defluorination. Furthermore, the compounds have suitable lipophilicity - a property required to penetrate the blood-brain barrier. Conclusion: These results showed that the instability of these compounds could cause a higher early phase/late phase ratio due to rapid clearance in the normal brain. The findings from this study suggest that these (18)F-labeled benzylideneaniline derivatives are feasible for the imaging of A beta plaques. (c) 2009 Elsevier Inc. All rights reserved.