In vivo measurement of plaque burden in a mouse model of Alzheimer's disease

PURPOSE: To demonstrate an MRI method for directly visualizing amyloid-beta (Abeta) plaques in the APP/PS1 transgenic (tg) mouse brain in vivo, and show that T1rho relaxation rate increases progressively with Alzheimer's disease (AD)-related pathology in the tg mouse brain. MATERIALS AND METHODS: We obtained in vivo MR images of a mouse model of AD (APP/PS1) that overexpresses human amyloid precursor protein, and measured T1rho via quantitative relaxometric maps. RESULTS: A significant decrease in T1rho was observed in the cortex and hippocampus of 12- and 18-month-old animals compared to their age-matched controls. There was also a correlation between changes in T1rho and the age of the animals. CONCLUSION: T1rho relaxometry may be a sensitive method for noninvasively determining AD-related pathology in APP/PS1 mice.     

Dimethylamino-fluorenes: ligands for detecting beta-amyloid plaques in the brain

Formation of beta-amyloid (Abeta) plaques in the brain is a major contributing factor in the pathogenesis of Alzheimer's disease (AD). Detection of Abeta plaques in the brain will be potentially useful in early diagnosis and monitoring the progression of the disease. A series of novel Abeta aggregate-specific ligands based on fluorenes, which are simple and rigid tricyclic molecules, are synthesized and characterized. Starting with 2- or 3-aminofluorenes, 1a-1f, the amino group was converted to the N,N-dimethylamino group (2a-2f) in excellent yield. It was found that 7-iodo-2-N,N-dimethylaminofluorene (2f) showed an extremely high binding affinity to preformed Abeta40 aggregates (K(i) = 0.9 nM). In vitro autoradiography study using brain sections obtained from transgenic mice (Tg2576) with [(125)I]2f showed exquisitely high specific binding to Abeta plaques. The same section also displayed an equivalent labeling when stained by Thioflavin-S, a commonly used fluorescent dye for Abeta plaques. When [(125)I]2f was injected intravenously into normal mice, it exhibited an excellent brain uptake. Taken together the data suggest that [(125)I]2f may be useful as an in vivo imaging agent to detect Abeta plaques in the brain.     

Labeling of cerebral amyloid beta deposits in vivo using intranasal basic fibroblast growth factor and serum amyloid P component in mice.

There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. METHODS: The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. RESULTS: Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in Tg mice without intranasal injection of the ligands. bFGF and SAP stained neurons around the rim of Abeta deposits and throughout the cortex in Tg mice. There was only weak staining of neurons in Tg mice without intranasal injection of bFGF and no staining of SAP in Tg mice without intranasal injection of SAP. No bFGF or SAP staining was evident in wild-type control mice. CONCLUSION: We report a novel noninvasive method for labeling Abeta plaques. This method may be modified for human studies using intranasal injection of radiolabeled ligands and imaging with SPECT or PET.     

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease.

The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD.     

Automatic segmentation of amyloid plaques in MR images using unsupervised support vector machines

Deposition of the β-amyloid peptide (Aβ) is an important pathological hallmark of Alzheimer's disease (AD). However, reliable quantification of amyloid plaques in both human and animal brains remains a challenge. We present here a novel automatic plaque segmentation algorithm based on the intrinsic MR signal characteristics of plaques. This algorithm identifies plaque candidates in MR data by using watershed transform, which extracts regions with low intensities completely surrounded by higher intensity neighbors. These candidates are classified as plaque or nonplaque by an unsupervised learning method using features derived from the MR data intensity. The algorithm performance is validated by comparison with histology. We also demonstrate the algorithm's ability to detect age-related changes in plaque load ex vivo in amyloid precursor protein (APP) transgenic mice that coexpress five familial AD mutations (5xFAD mice). To our knowledge, this study represents the first quantitative method for characterizing amyloid plaques in MRI data. The proposed method can be used to describe the spatiotemporal progression of amyloid deposition, which is necessary for understanding the evolution of plaque pathology in mouse models of Alzheimer's disease and to evaluate the efficacy of emergent amyloid-targeting therapies in preclinical trials.     

Longitudinal assessment of Alzheimer's beta-amyloid plaque development in transgenic mice monitored by in vivo magnetic resonance microimaging

PURPOSE: To assess the development of beta-amyloid (Abeta) plaques in the brain with age in the transgenic mouse model of Alzheimer's disease (AD) pathology by in vivo magnetic resonance microimaging (microMRI). MATERIALS AND METHODS: Live transgenic mice (Tg2576) and nontransgenic littermates (control) were studied at regular intervals between the ages of 12 and 18 months. Plaques were visualized using a T(2)-weighted rapid acquisition with relaxation enhancement (RARE) sequence. Changes in T(2) relaxation times were followed using a multislice multiecho (MSME) sequence. Plaque load and numerical density in MR images were calculated using SCIL image software. RESULTS: Abeta plaques were clearly detected with the T(2)-weighted RARE sequence in the hippocampal and cortical regions of the brain of Tg2576 mice but not in control mice. Following the plaque development in the same animals with age showed that plaque area, number, and size increased markedly, while T(2) relaxation time showed a decreasing trend with age. CONCLUSION: These results demonstrate that microMRI is a viable method for following the development of Abeta plaques in vivo, and suggest that this method may be feasible for assessing the effect of therapeutic interventions over time in the same animals.     

Passive staining: a novel ex vivo MRI protocol to detect amyloid deposits in mouse models of Alzheimer's disease.

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). This study evaluated a novel microMRI strategy based on "passive staining" of brain samples by gadoteric acid. The protocol was tested at 4.7 T on control animals and APP/PS1 mice modeling AD lesions. T(1) was strongly decreased in passively stained brains. On high-resolution 3D gradient echo images, the contrast between the cortex and subcortical structures was highly improved due to a T2* effect. The brains of APP/PS1 mice revealed plaques as hypo-intense spots. They appeared larger in long compared to short TE images. This suggests that, after passive staining, plaques caused a susceptibility effect. This easily performed protocol is a complementary method to classic histology to detect the 3D location of plaques. It may also be used for the validation of in vivo MRI protocols for plaque detection by facilitating registration with histology via post mortem MRI.     

Benzofuran derivatives as Abeta-aggregate-specific imaging agents for Alzheimer's disease

The purpose of this study is to develop potential I-123 labeled diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD). Formation and accumulation of aggregates of beta-amyloid (Abeta) peptides in the brain are critical factors in the development and progression of AD. Small molecule-based benzofuran derivatives were designed and synthesized. Both 5- and 6-iodobenzofuran derivatives displayed excellent competition for I-125 TZDM binding to Abeta40 aggregates with K(i) values in the subnanomolar range. The radioiodinated ligands, with a high specific activity, were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives using hydrogen peroxide as the oxidant in high yields (60-80%) and with high radiochemical purities (greater than 95%). After an iv injection, all four radioiodinated ligands displayed high brain uptakes ranging from 0.5 to 1.5% initial dose/organ in normal mice. The radioactivity washed out from the mouse brain slowly (less than 50% at 2 h post injection), suggesting high in vivo non-specific binding. In conclusion, the benzofuran ligands displayed excellent binding affinity for Abeta aggregates. The long retention of these ligands in the normal mouse brain suggests that there may be high binding for these probes in the brain not associated with Abeta plaques. Additional modifications are necessary to improve the in vivo imaging properties for plaque detection.     

In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent.

One of the cardinal pathologic features of Alzheimer's disease (AD) is the formation of senile, or amyloid, plaques. Transgenic mice have been developed that express one or more of the genes responsible for familial AD in humans. Doubly transgenic mice develop "human-like" plaques, providing a mechanism to study amyloid plaque biology in a controlled manner. Imaging of labeled plaques has been accomplished with other modalities, but only MRI has sufficient spatial and contrast resolution to visualize individual plaques noninvasively. Methods to optimize visualization of plaques in vivo in transgenic mice at 9.4 T using a spin echo sequence based on adiabatic pulses are described. Preliminary results indicate that a spin echo acquisition more accurately reflects plaque size, while a T2* weighted gradient echo sequence reflects plaque iron content, not plaque size. In vivo MRI-ex vivo MRI-in vitro histologic correlations are provided. Histologically verified plaques as small as 50 microm in diameter were visualized in living animals. To our knowledge this work represents the first demonstration of noninvasive in vivo visualization of individual AD plaques without the use of a contrast agent.     

Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of β-amyloid plaques in Alzheimer's disease

Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for β-amyloid (Aβ) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for Aβ(1-42) aggregates (K(i) = 9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [(125)I]12, labeled Aβ plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [(125)I]12 showed high uptake [4.14 percent injected dose per gram (% ID/g) at 2 min] into and rapid clearance (0.15% ID/g at 60 min) from the brain, which may bring about a good signal-to-noise ratio and therefore achieve highly sensitive detection of Aβ plaques. In addition, [(125)I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [(125)I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with (123)I, it may be a useful SPECT imaging agent for Aβ plaques in the brain of living AD patients.     

Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents.

The visualization of beta-amyloid plaque deposition in brain, a key feature of Alzheimer's disease (AD), is important for the evaluation of disease progression and the efficacy of therapeutic interventions. In this study, beta-amyloid plaques in the PS/APP transgenic mouse brain, a model of human AD pathology, were detected using MR microscopy without contrast reagents. beta-Amyloid plaques were clearly visible in the cortex, thalamus, and hippocampus of fixed brains of PS/APP mice. The distribution of plaques identified by MRI was in excellent agreement with those found in the immunohistological analysis of the same brain sections. It was also demonstrated that image contrast for beta-amyloid plaques was present in freshly excised nonfixed brains. Furthermore, the detection of beta-amyloid plaques was achieved with a scan time as short as 2 hr, approaching the scan time considered reasonable for in vivo imaging.     

MR microimaging of amyloid plaques in Alzheimer's disease transgenic mice

INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. DISCUSSION AND CONCLUSION: Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas.     

Synthesis and evaluation of benzothiophene derivatives as ligands for imaging beta-amyloid plaques in Alzheimer's disease

The imaging of the distribution of beta-amyloid (Abeta) plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease (AD). Here, we synthesized novel benzothiophene derivatives and labeled them with (18)F for the potential diagnostic imaging of AD patients using positron emission tomography. The K(i) values of benzothiophene derivatives were evaluated by competitive binding assay using 2-(3'-[(125)I]iodo-4'-N-methylaminophenyl)benzothiazole as a radioligand and Abeta(1-40) or Abeta(1-42) aggregates as receptors. All synthesized benzothiophene derivatives showed high binding affinities (K(i)=0.28-6.50 nM) to both Abeta(1-40) and Abeta(1-42) aggregates. Binding affinities were increased by O-alkylation or N-alkylation of 2-(4'-hydroxyphenyl)benzothiophene or 2-(4'-aminophenyl)benzothiophene. Biodistribution studies of 2-(4'-O-(2'-[(18)F]fluoroethyl)hydroxyphenyl)benzothiophene ([(18)F]) and 2-(4'-O-(3'-[(18)F]fluoropropyl)hydroxyphenyl)benzothiophene ([(18)F]) in normal mice were performed after intravenous injection through the tail vein. In biodistribution data, [(18)F] and [(18)F] showed high initial brain uptakes at 2 min (5.2+/-0.4% and 3.3+/-0.2% ID/g, respectively), and brain activities washed out to 2.0+/-0.2% and 0.5+/-0.1% ID/g at 4 h, respectively. In conclusion, benzothiophene derivatives showed excellent binding affinities for Abeta aggregates and high initial brain uptakes in normal mice.     

2-(2-[2-Dimethylaminothiazol-5-yl]ethenyl)-6- (2-[fluoro]ethoxy)benzoxazole: a novel PET agent for in vivo detection of dense amyloid plaques in Alzheimer's disease patients.

Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET. METHODS: The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis. RESULTS: BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils. CONCLUSION: These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.     

Transverse relaxation time reflects brain amyloidosis in young APP/PS1 transgenic mice.

Amyloid deposits are one of the hallmarks of Alzheimer's disease (AD), one of the most devastating neurodegenerative disorders. In transgenic mice modeling Alzheimer's pathology, the MR transverse relaxation time (T(2)) has been described to be modulated by amyloidosis. This modification has been attributed to the age-related iron deposition that occurs within the amyloid plaques of old animals. In the present study, young APP/PS1 transgenic mice without histochemically detectable iron in the brain were specifically studied. In vivo measurements of T(2) in the hippocampus, at the level of the subiculum, were shown to reflect the density of amyloid plaques. This suggests that T(2) variations can be induced solely by aggregated amyloid deposits in the absence of associated histologically-detectable iron. Thus T(2) from regions with high amyloid load, such as the subiculum, is particularly well suited for following plaque deposition in young animals, i.e., at the earliest stages of the pathological process.     

Impact of amyloid imaging on drug development in Alzheimer's disease

Imaging agents capable of assessing amyloid-beta (Abeta) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Abeta plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Abeta imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Abeta plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Abeta plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.     

Biphenyls labeled with technetium 99m for imaging beta-amyloid plaques in the brain

Formation and accumulation of excess aggregates of beta-amyloid (Abeta) plaques in the brain are critical factors contributing to the development and progression of Alzheimer's disease (AD). There is an urgent need for in vivo imaging agents that can specifically demonstrate the location and density of Abeta plaques in the brain. The aim of this study was to develop potential technetium 99m (99mTc)-labeled diagnostic imaging agents specific for the detection of Abeta plaques. Based on previously obtained Abeta plaque-specific biphenyls containing a p-N, N-dimethylaminophenyl group, a series of 99mTc and Re-N2S2-biphenyl derivatives was prepared. The stable neutral and lipophilic 99mTc complexes, [99mTc]19 and [99mTc]23, A+B, were successfully obtained. As surrogates for the 99mTc complexes, the corresponding surrogates, Re complexes of 23, were also prepared. Surprisingly, it was found that the Re complexes showed distinctively different retention profiles as compared with the corresponding 99mTc complexes. Biodistribution studies indicated that [99mTc]23A readily passed through the blood-brain barrier (1.18% dose/brain at 2 min) in contrast to the low brain penetration of [99mTc]19 (0.29% dose/brain at 2 min). Initial results suggested that [99mTc]23A showed selective binding to the Abeta plaque-like structures in the brain sections from transgenic mice but not in the postmortem human brain tissue of patients with confirmed AD. The results provide encouraging evidence that development of a 99mTc-labeled agent for imaging Abeta plaques in the brain may be feasible. Caution should be taken when comparing these 99mTc complexes with the corresponding surrogates--the Re complexes.     

18F-labeled styrylpyridines as PET agents for amyloid plaque imaging

Positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain is a potentially valuable tool for studying the pathophysiology of Alzheimer's disease (AD). It may also be applicable for measuring the effectiveness of therapeutic drugs aimed at lowering Abeta plaques in the brain. We have successfully reported a series of 18F-labeled fluoropegylated stilbenes for PET imaging studies. Encouraging results clearly demonstrated the usefulness of 18F-labeled stilbenes as potential Abeta plaque-imaging agents. In the present study, we applied a similar approach to a styrylpyridine backbone structure. Among all derivatives examined, (E)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-5-(4-dimethylaminostyryl)-pyridine (2) displayed high binding affinity in postmortem AD brain homogenates (Ki=2.5+/-0.4 nM, with [125I]IMPY as radioligand). No-carrier-added [18F]2 was successfully prepared by [18F]fluoride displacement of the corresponding tosylate precursor with a high labeling yield (30-40%) and a high radiochemical purity (>99%). Specific activity at the end of synthesis was determined to be 1500-2000 Ci/mmol. The tracer [18F]2 showed adequate lipophilicity (log P=3.22). In vivo biodistribution of [18F]2 in normal mice exhibited excellent initial brain penetration and rapid washout (7.77% and 1.03% dose/g in the brain at 2 and 30 min after intravenous injection, respectively)--properties that are highly desirable for Abeta-plaque-specific brain imaging agents. Autoradiography of AD brain sections and homogenate binding with postmortem AD brain tissues confirmed the high binding signal of [18F]2 due to the presence of Abeta plaques. These preliminary results suggest that novel PET tracers may be potentially useful for the imaging of Abeta plaques in the living human brain.     

In vivo MR imaging of bone marrow cells trafficking to atherosclerotic plaques

PURPOSE: To develop a magnetic resonance imaging (MRI)-based method to monitor in vivo trafficking of bone marrow (BM) cells to atherosclerotic lesions. MATERIALS AND METHODS: BM cells from LacZ-transgenic mice were labeled with a superparamagnetic iron oxide (Feridex) and then transplanted into ApoE(-/-) recipient mice that were fed an atherogenic diet. Twenty-four ApoE(-/-) mice were divided into three study groups: 1) group I with Feridex-labeled BM transplantation (BMT) cells (N = 9), 2) group II with unlabeled BMT cells (N = 10), and 3) group III with no BMT cells (N = 5). Migrated Feridex/LacZ-BM cells to atherosclerotic aortic walls were monitored in vivo using a 4.7T MR scanner and correlated with histopathological findings. RESULTS: In group I with Feridex-BMT cells, histology examination displayed plaques in five of nine animals. In four of these five animals, in vivo MRI showed large MR signal voids of the aorta walls (due to the "blooming" effect of migrated Feridex-BM cells in plaques), which were correlated with Feridex- and/or LacZ-positive cells detected in the atherosclerotic lesions. No signal voids could be visualized in the two control animal groups (groups II and III). CONCLUSION: This study demonstrates the potential use of in vivo MRI to monitor the trafficking of magnetically labeled BM cells to atherosclerotic lesions.     

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.