Synthesis and evaluation of 18F-labeled 2-phenylbenzothiazoles as positron emission tomography imaging agents for amyloid plaques in Alzheimer's disease.
Imaging agents targeting amyloid beta (Abeta) may be useful for early diagnosis and follow-up of treatment of patients with Alzheimer's disease (AD). Three of five tested 2-(4'-fluorophenyl)-1,3-benzothiazoles displayed high binding affinities for Abeta plaques in AD human brain homogenates (K(i) between 2.2 and 22.5 nM). They all contained the (18)F-label directly attached to the aromatic ring and were synthesized starting from the nitro precursor. Determination of the partition coefficient, biodistribution studies in normal mice, and in vivo microPET studies in normal rats showed that their initial brain uptake was high and brain washout was fast. The most promising compound [(18)F]5, or 6-methyl-2-(4'-[(18)F]fluorophenyl)-1,3-benzothiazole, seemed to be metabolically stable in the brain, and its plasma radiometabolites, which do not cross the blood-brain barrier, were determined. The preliminary results strongly suggest that this new fluorinated compound is a promising candidate as an Abeta plaque imaging agent for the study of patients with AD.
Serdons
Kim
K
Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium. kim.serdons@pharm.kuleuven.be
Terwinghe
Christelle
C
Vermaelen
Peter
P
Van Laere
Koen
K
Kung
Hank
H
Mortelmans
Luc
L
Bormans
Guy
G
Verbruggen
Alfons
A
D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D014018:Tissue Distribution
C550366:6-methyl-2-(4'-fluorophenyl)-1,3-benzothiazole; D052160:Benzothiazoles; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D013844:Thiazoles