Radiosynthesis and evaluation of [11C]BTA-1 and [11C]3'-Me-BTA-1 as potential radiotracers for in vivo imaging of beta-amyloid plaques.
OBJECTIVE
To evaluate the in vitro and in vivo characteristics of [N-methyl-(11)C]2-(4'-(methylaminophenyl)-benzothiazole ([(11)C]BTA-1) as well as [N-methyl-(11)C]2-(3'-methyl-4'-(methylamino)phenyl)-benzothiazole ([(11)C]3'-Me-BTA-1) as diagnostic markers of amyloid-beta (Abeta) in Alzheimer's disease (AD).


METHODS
Brain uptake and clearance was determined in wild-type mice. Binding affinities (K(i)) of [(11)C]BTA-1 and [(11)C]3'-Me-BTA-1 for aggregated Abeta(1-40) fibrils were assessed. Autoradiography was performed on brain sections of AD patients. To demonstrate binding specificity in vivo BTA-1 was injected i.p. in transgenic mice (Tg2576). Brain sections were analysed consecutively. Additionally, a [(11)C]BTA-1 PET study of an AD patient and a healthy control was performed.


RESULTS
In mice brain uptake and clearance of [(11)C]BTA-1 is compatible with the half life of (11)C (2 min: 12.7 % ID/g; 30 min: 4.6% ID/g). In contrast clearance rate of [(11)C]3'-Me-BTA-1 is too slow (2 min 4% ID/g; 30 min 12% ID/g) to achieve sufficient clearance of free and non specifically bound radioactivity. K(i) of [(11)C]BTA-1 is 11 nmol/l and that of [(11)C]3'-Me-BTA-1 27 nmol/l. Both radioligands label Abeta selectively and specifically in AD patients and transgenic mice in vitro. The in vivo stained brain sections show a labelling of Abeta plaques. The AD patient has a higher prefrontal, parietal and striatal [(11)C]BTA-1 accumulation than the healthy control. Metabolite analysis revealed approximately 75% intact [(11)C]BTA-1 after 30min in plasma.[(11)C]BTA-1 is favourable for in vivo imaging of Abeta due to its rapid brain entry, sufficient clearance and good binding affinity for Abeta.


CONCLUSIONS
The ability to label Abeta plaques in vivo in human subjects supports the suitability of [(11)C]BTA-1 as a plaque imaging agent.
Neumaier
B
B
Department of Nuclear Medicine, University Hospital Leuven, Herestraat 49, Leuven, Belgium.
Deisenhofer
S
S
Fürst
D
D
von Arnim
C A F
CA
Thees
S
S
Buck
A K
AK
Glatting
G
G
Landwehrmeyer
G B
GB
Krause
B J
BJ
Müller
H D
HD
Sommer
C
C
Reske
S N
SN
Mottaghy
F M
FM
D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D062366:para-Aminobenzoates
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; C527159:N-methyl-(11)C)2-(4'-(methylaminophenyl)benzothiazole; D019275:Radiopharmaceuticals; D062366:para-Aminobenzoates; C015668:4-aminomethylbenzoic acid; D010129:4-Aminobenzoic Acid