¹⁸F-Labeled benzylideneaniline derivatives as new ligands for β-amyloid plaque imaging in Alzheimer's disease

Abstract 

Introduction

Noninvasive early detection of β-amyloid (Aβ) plaques might be useful for the treatment of patients with Alzheimer's disease (AD). We herein describe the synthesis of ¹⁸F-labeled benzylideneaniline derivatives using a novel labeling approach for imaging Aβ plaques in AD patients.

Methods

Benzylidenaniline derivatives were synthesized by reacting fluorobenzaldehyde and corresponding aniline derivatives. Fluorobenzaldehyde was labeled with ¹⁸F by incubating [¹⁸F]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 ∼7.4). The K_i values of amine-containing benzylideneaniline derivatives for Aβ_1–40 and Aβ_1–42 aggregates were 26–78 nM. These ¹⁸F-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 ¹⁸F-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 ¹⁸F-labeled benzylideneaniline derivatives are feasible for the imaging of Aβ plaques.

Keywords: Positron emission tomography, PET, Fluorobenzaldehyde, Amyloid plaque