(18)F-Labeled benzylideneaniline derivatives as new ligands for beta-amyloid plaque imaging in Alzheimer's disease.
BACKGROUND
Noninvasive early detection of beta-amyloid (Abeta) 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 Abeta plaques in AD patients.


METHODS
Benzylidenaniline 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 approximately 7.4). The K(i) values of amine-containing benzylideneaniline derivatives for Abeta(1-40) and Abeta(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.


CONCLUSIONS
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 Abeta plaques.
Lee
Hak Jeong
HJ
Department of Nuclear Medicine, Seoul National University College of Medicine and Institute of Radiation Medicine, Jongno-gu, Seoul 110-744, South Korea. yes2hack@snu.ac.kr
Jeong
Jae Min
JM
Rai
Ganesha
G
Lee
Yun-Sang
YS
Chang
Young Soo
YS
Kim
Young Ju
YJ
Kim
Hyung Woo
HW
Lee
Dong Soo
DS
Chung
Jung Key
JK
Mook-Jung
Inhee
I
Lee
Myung Chul
MC
D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001597:Benzylidene Compounds / Q000378:metabolism*; D001812:Blood-Brain Barrier; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D001597:Benzylidene Compounds; D005462:Fluorine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)