11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer's disease.
A series of stilbene derivatives as potential diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of the stilbenes were successfully achieved by a simple Wadsworth-Emmons reaction between diethyl (4-nitrobenzyl)phosphonate and 4-methoxybenzaldehyde. 4-N,N-dimethylamino-4'-methyoxy and the corresponding 4-N-monomethylamino-, 4'-hydroxy stilbenes showed good binding affinities towards Abeta aggregates in vitro (K(i) < 10 nM). The (11)C labeled 4-N-methylamino-4'-hydroxystilbene, [(11)C]4, was prepared by (11)C methylation of 4-amino-4'-hydroxystilbene. The [(11)C]4 displayed a moderate lipophilicity (log P = 2.36), and showed a very good brain penetration and washout from normal rat brain after an iv injection. In vitro autoradiography of transgenic AD mouse brain sections showed a high specific labeling of beta-amyloid plaques, whereas the control sections showed no binding. Taken together the data suggest that a relatively simple stilbene derivative, [(11)C]4, N-[(11)C]methylamino-4'-hydroxystilbene, may be useful as a positron emission tomography (PET) imaging agent for mapping Abeta plaques in the brain of patients with Alzheimer's disease.
Ono
Masahiro
M
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Wilson
Alan
A
Nobrega
Jose
J
Westaway
David
D
Verhoeff
Paul
P
Zhuang
Zhi-Ping
ZP
Kung
Mei-Ping
MP
Kung
Hank F
HF
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
D016229:Amyloid beta-Peptides; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D013267:Stilbenes