PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease.
OBJECTIVE
The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD).


METHODS
PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S.


RESULTS
TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice.


CONCLUSIONS
Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.
Toyama
Hiroshi
H
Department of Radiology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake, Toyoake, 470-1192, Aichi, Japan. htoyama@fujita-hu.ac.jp
Ye
Daniel
D
Ichise
Masanori
M
Liow
Jeih-San
JS
Cai
Lisheng
L
Jacobowitz
David
D
Musachio
John L
JL
Hong
Jinsoo
J
Crescenzo
Mathew
M
Tipre
Dnyanesh
D
Lu
Jian-Qiang
JQ
Zoghbi
Sami
S
Vines
Douglass C
DC
Seidel
Jurgen
J
Katada
Kazuhiro
K
Green
Michael V
MV
Pike
Victor W
VW
Cohen
Robert M
RM
Innis
Robert B
RB
D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013844:Thiazoles / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D019275:Radiopharmaceuticals; D013844:Thiazoles