Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and thus, the in vivo imaging of plaques and tangles would be beneficial for the early diagnosis of AD. It has been suggested that 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (curcumin) may be responsible for low age-adjusted prevalence of AD in India. In the present study, eight novel derivatives of curcumin and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (dehydrozingerone) were synthesized and their binding affinities for beta-amyloid (Abeta) aggregates were measured. Of these ligands, fluoropropyl-substituted curcumin (8) showed the highest binding affinity (Ki=0.07 nM), and therefore, 8 was radiolabeled and evaluated as a potential probe for Abeta plaque imaging. Partition coefficient measurement and biodistribution in normal mice demonstrated that [18F]8 has a suitable lipophilicity and reasonable initial brain uptake. Metabolism studies also indicated that [18F]8 is metabolically stable in the brain. These results suggest that [18F]8 is a suitable radioligand for Abeta plaque imaging.     

New diphenylacetylenes as probes for positron emission tomographic imaging of amyloid plaques

A series of 18F fluoropegylated diphenylacetylenes as probes for binding to Abeta plaques were successfully prepared. These relatively rigid acetylenes, 12a, 12b, 14a, and 14b, displayed high binding affinities in postmortem AD brain homogenates (Ki ranging from 1.2 to 2.9 nM). In vivo biodistribution in normal mice exhibited excellent initial brain penetrations (4.42, 4.55, 5.41, and 6.78% dose/g at 2 min for [18F]12a, 12b, 14a, and 14b, respectively). [18F]12b and [18F]14b, with a longer fluoropegylated unit, that is, n=3, showed faster brain washout at 30 min postinjection (0.42 and 1.57% dose/g) as compared to the shorter fluoropegylated chain ligands, that is, [18F]12a and [18F]14a (1.03 and 3.69% dose/g). Autoradiography and homogenate binding confirmed the high binding signal due to Abeta plaques. These preliminary results suggest that the novel diphenylacetylenes may be potentially useful for imaging of Abeta plaques in the brain of patients with Alzheimer's disease.     

Quick assembly of 1,4-diphenyltriazoles as probes targeting beta-amyloid aggregates in Alzheimer's disease

Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to Abeta aggregates (Ki = 4-30 nM), were conveniently assembled by "click chemistry." Two radioiodinated probes, [125I]10a and [125I]10b, and two radiofluorinated probes, [18F]17a and [18F]17b, exhibited moderate lipophilicities and showed excellent initial brain penetrations and fast washouts from the normal mouse brain. In vitro autoradiography of postmortem AD brain sections and homogenates showed that these triazoles were binding to Abeta plaques. Preliminary results strongly suggest that use of click chemistry, which led to a 1,4-diphenyltriazole-based core, is a highly convenient and flexible approach for assembling novel imaging agents for targeting Abeta aggregates in senile plaques in the living human brain.     

Novel styrylpyridines as probes for SPECT imaging of amyloid plaques

We report a series of radioiodinated styrylpyridines as single photon emission computed tomography probes for imaging Abeta plaques in the brain of patients with Alzheimer's disease (AD). In vitro binding showed that all of the styrylpyridines displayed very good binding affinities in postmortem AD brain homogenates (Ki = 3.6 to 15.5 nM). No-carrier-added samples of 13a, 13b, 16a, 16b, and 16e (radioiodinated with 125I) were successfully prepared. The in vivo biodistribution in normal mice, at 2 min after injection, showed excellent initial brain penetrations (4.03, 6.22, 5.43, and 8.04% dose/g for [125I]13a, 13b, 16a, and 16b, respectively). Furthermore, in vitro autoradiography of AD brain sections showed that the high binding signal was specifically due to the presence of Abeta plaques. Taken together, these results strongly suggest that these styrylpyridines are useful for imaging Abeta plaques in the living human brain.     

Novel 18F-labeled benzofuran derivatives with improved properties for positron emission tomography (PET) imaging of β-amyloid plaques in Alzheimer's brains

In vivo imaging of β-amyloid plaques in the brain may lead to the early diagnosis of Alzheimer's disease (AD) and monitoring of the progression and effectiveness of treatment. In the present study, we report on the development of two potential PET probes, [(18)F]FPYBF-2 ([(18)F]10) and [(18)F]FPHBF-2 ([(18)F]21), for imaging of β-amyloid plaques in AD brain. In experiments in vitro, 10 and 21 displayed high affinity for Aβ(1-42) aggregates (K(i) = 2.41 and 3.85 nM, respectively). In biodistribution experiments using normal mice, they displayed high uptake in the brain (7.38 and 8.18%?ID/g at 2 min postinjection, respectively), and the radioactivity washed out from the brain rapidly (3.15 and 3.87%?ID/g at 60 min postinjection, respectively), which is highly desirable for β-amyloid imaging agents. In vivo, they clearly labeled β-amyloid plaques in Tg2576 mice. Furthermore, the specific labeling of β-amyloid plaques by 10 and 21 was observed in autoradiographs of sections of autopsied AD brain. These new fluorinated benzofuran derivatives are promising PET probes for imaging cerebral β-amyloid plaques.     

Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.     

Structure–Activity Relationships and in Vivo Evaluation of Quinoxaline Derivatives for PET Imaging of β-Amyloid Plaques

相似文献   

Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents

The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition.     

Radioiodinated flavones for in vivo imaging of beta-amyloid plaques in the brain

In vivo imaging of beta-amyloid (A beta) peptide aggregates in the brain may lead to early detection of Alzheimer's disease (AD) and monitoring of the progression and effectiveness of AD treatment. The purpose of this study was to develop novel amyloid imaging agents based on flavone as a core structure. Radioiodinated flavone derivatives were designed and synthesized. The binding affinities of flavone derivatives for A beta aggregates varied from 13 to 77 nM. When in vitro plaque labeling was carried out using post-mortem AD brain sections, all flavones intensely stained not only amyloid plaques but also cerebrovascular amyloids. In biodistribution studies using normal mice, they displayed high brain uptakes ranging from 3.2 to 4.1% ID/g at 2 min postinjection. The radioactivity washed out from the brain rapidly (0.5-1.9% ID/g at 30 min), which is highly desirable for amyloid imaging agents. The results in the study suggest that these classes of radioiodinated flavones may be useful candidates as potential imaging agents for amyloid plaques.     

Radioligand development for PET imaging of beta-amyloid (Abeta)--current status

Two of the main pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques and neurofibrillary tangles. Significant evidence supports a critical and probable causative role of beta amyloid (Abeta) plaque formation. Since neuroprotective treatments are typically most effective at early stages of injury, the detection and measurement of Abeta load in living brain should be performed at early and perhaps even presymptomatic stages of AD. Two primary targets of molecular imaging research with positron emission tomography (PET) are to develop surrogate markers (radioligands) for assessing disease progression and for monitoring the efficacy of developmental therapeutics. Here, we review the current status of radioligand development for PET imaging of Abeta aggregates. General structure-activity relationships have emerged, including the identification of at least three different ligand binding sites in various Abeta aggregates and recognition of the general structural requirements for ligand binding at each site. Also a few radioligands applicable to imaging Abeta plaques in living human brain with positron emission tomography (PET) have emerged, including [(11)C]PIB, [(11)C]SB-13 and [(18)F]FDDNP.     

Novel benzofuran derivatives for PET imaging of beta-amyloid plaques in Alzheimer's disease brains

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.     

Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates

We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to Abeta aggregates, cross the intact blood-brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of Abeta(1-40) and Abeta(1-42) peptides, commonly associated with plaques in the brain of people with Alzheimer's disease (AD), were developed. Two 125I-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two 125I-labeled thioflavins, 2-[4'-(dimethylamino)phenyl]-6-iodobenzothiazole, 18a (TZDM), and 2-[4'-(4'-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, 18b (TZPI), were prepared at a high specific activity (2200 Ci/mmol). In vitro binding studies of these ligands showed excellent binding affinities with Kd values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of Abeta(1-40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of Abeta(1-42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on Abeta(1-40) and Abeta(1-42) aggregates, which are mutually exclusive, were observed for styrylbenzenes and thioflavins. Autoradiography studies of postmortem brain sections of a patient with Down's syndrome known to contain primarily Abeta(1-42) aggregates in the brain showed that both [(125)I]18a and [125I]18b labeled these brain sections, but [125I]13, selective for Abeta(1-40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [125I]18a and [(125)I]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [125I]12 and [125I]13. These findings strongly suggest that the new radioiodinated ligands, [125I]12 (ISB), [125I]13 (IMSB), [125I]18a (TZDM), and [125I]18b (TZPI), may be useful as biomarkers for studying Abeta(1-40) as well as Abeta(1-42) aggregates of amyloidogenesis in AD patients.     

2-(2'-((dimethylamino)methyl)-4'-(fluoroalkoxy)-phenylthio)benzenamine derivatives as serotonin transporter imaging agents

A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4'-position on phenyl ring B of 2-(2'-((dimethylamino)methyl)-4'-(fluoroalkoxy)phenylthio)benzenamine (4'-2-fluoroethoxy derivatives 28-31 and 4'-3-fluoropropoxy derivatives 40-42) were prepared and tested as serotonin transporter (SERT) imaging agents. The new ligands displayed high binding affinities to SERT (Ki ranging from 0.03 to 1.4 nM). The corresponding 18F labeled compounds, which can be prepared readily, showed excellent brain uptake and retention after iv injection in rats. The hypothalamus region showed high uptake values between 0.74% and 2.2% dose/g at 120 min after iv injection. Significantly, the hypothalamus to cerebellum ratios (target to nontarget ratios) at 120 min were 7.8 and 7.7 for [18F]28 and [18F]40, respectively. The selective uptake and retention in the hypothalamus, which has a high concentration of SERT binding sites, demonstrated that [18F]28 and [18F]40 are promising positron emission computed tomography imaging agents for mapping SERT binding sites in the brain.     

Multidentate (18)F-polypegylated styrylpyridines as imaging agents for Aβ plaques in cerebral amyloid angiopathy (CAA)

β-Amyloid plaques (Aβ plaques) in the brain are associated with cerebral amyloid angiopathy (CAA). Imaging agents that could target the Aβ plaques in the living human brain would be potentially valuable as biomarkers in patients with CAA. A new series of (18)F styrylpyridine derivatives with high molecular weights for selectively targeting Aβ plaques in the blood vessels of the brain but excluded from the brain parenchyma is reported. The styrylpyridine derivatives, 8a-c, display high binding affinities and specificity to Aβ plaques (K(i) = 2.87, 3.24, and 7.71 nM, respectively). In vitro autoradiography of [(18)F]8a shows labeling of β-amyloid plaques associated with blood vessel walls in human brain sections of subjects with CAA and also in the tissue of AD brain sections. The results suggest that [(18)F]8a may be a useful PET imaging agent for selectively detecting Aβ plaques associated with cerebral vessels in the living human brain.     

A New Highly Deuterated [18F]AV-45, [18F]D15FSP,for Imaging β-Amyloid Plaques in the Brain

[¹⁸F]AV-45 (florbetapir f18, Amyvid) is an FDA-approved PET imaging agent targeting Aβ plaques in the brain for diagnosis of Alzheimer’s disease (AD). Its metabolites led to a high background in the brain and large bone uptake of [¹⁸F]F^–, produced from dealkylation of the PEG chain. To slow down the in vivo metabolism, we report the design, synthesis, and evaluation of a highly deuterated derivative, [¹⁸F]D15FSP, and compared it with N-methyl-deuterated [¹⁸F]D3FSP and nondeuterated [¹⁸F]AV-45. D15FSP displayed excellent binding affinity (K_i = 7.52 nM) to Aβ aggregates. In vitro autoradiography of [¹⁸F]D15FSP, [¹⁸F]D3FSP, and [¹⁸F]AV-45 showed excellent binding to Aβ plaques in human AD brain sections. Biodistribution studies displayed lower bone uptake at 120 min for [¹⁸F]D15FSP compared to that for [¹⁸F]D3FSP and [¹⁸F]AV-45 (1.44 vs 4.23 and 4.03%ID/g, respectively). As the highly deuterated [¹⁸F]D15FSP displayed excellent Aβ binding affinity, high initial brain penetration, and lower bone retention, it might be suitable for PET imaging in detecting Aβ plaques.     

苯并噻唑希夫碱类化合物的合成及其与β-淀粉样蛋白结合性能的研究

阿尔茨海默病(Alzheimer’s disease,AD)是一种神经退行性疾病。随着人口老龄化,发病率逐年增高,不仅严重危害着老年人的健康,而且给家庭、社会带来了巨大的经济和人力负担。在我国1.3亿老年人中,痴呆患者600～700万人,发病率在5%以上,约占世界总病例的1/4,成为世界老年痴呆症第一大国[1]。AD常隐匿起病,逐渐出现记忆力减退、认知     

Synthesis and evaluation of ¹⁸F-labeled styryltriazole and resveratrol derivatives for β-amyloid plaque imaging

In the present study, a styryltriazole and four resveratrol derivatives were synthesized as candidates for β-amyloid (Aβ) plaque imaging. On the basis of their binding affinities to Aβ(1-42) aggregates, the styryltriazole (1, K(i) = 12.8 nM) and one resveratrol derivative (5, K(i) = 0.49 nM) were labeled with (18)F. In normal mice, tissue distribution of [(18)F]5 showed good initial brain uptake (3.26% ID/g at 2 min) but slow wash-out from brains (2-to-60 min uptake ratio: 2.9). Furthermore, it underwent in vivo metabolic defluorination (1.88% ID/g at 2 min and 9.73% ID/g at 60 min). In contrast, [(18)F]1 displayed high initial brain uptake (5.38% ID/g at 2 min) with rapid wash-out from brains (0.52% ID/g at 60 min; 2-to-60 min uptake ratio: 10.3). These results indicate that [(18)F]1 has in vivo kinetics comparable to PET radiopharmaceuticals currently under commercial development, demonstrating that [(18)F]1 is a desirable PET radioligand for Aβ plaque imaging.     

Development of fluorine-18-labeled 5-HT1A antagonists

We have synthesized five fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-N-(2-pyridyl)cyclohe xaneca rboxamide (4a), using various acids in place of the cyclohexanecarboxylic acid (CHCA, 2a) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB, 2b), 4-fluoro-3-methylbenzoic acid (MeFB, 2c), trans-4-fluorocyclohexanecarboxylic acid (FC, 2d), 4-(fluoromethyl)benzoic acid (FMeB, 2e), and 3-nitro-4-(fluoromethyl)benzoic acid (NFMeB, 2f) (see Scheme 1). These compounds were radiolabeled with fluorine-18, and their biological properties were evaluated in rats and compared with those of [11C]carbonyl WAY 100635 ([carbonyl-11C]4a). [Carbonyl-11C]4a cleared the brain with a biological half-life averaging 41 min. The metabolite-corrected blood radioactivity had a half-life of 29 min. [18F]FCWAY ([18F]4d) gave half-lives and intercepts comparable to [carbonyl-11C]4a in the brain, but the blood clearance was faster. [18F]FBWAY ([18F]4b) showed an early rapid net efflux from the whole brain, clearing with a biological half-life of 35 min. The metabolite-corrected blood half-life was 41 min. The comparable whole brain and blood half-lives for Me[18F]FBWAY ([18F]4c) were 16 and 18 min, respectively. For each compound, the corresponding carboxylic acid was identified as a major metabolite in blood. Fluoride was also found after injection of [18F]4d. However, for all compounds there was a good correlation (R > 0.97) between the differential uptake ratio (DUR, (%ID/g) x body weight (g)/100) in individual rat brain regions at 30 min after injection and the concentration of receptors as determined by in vitro quantitative autoradiography in rat. Specific binding ratios [region of interest (ROI)/cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-11C]4a and [18F]4d compared to [18F]4b and [18F]4c. [18F]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-11C]4a. Fifty nanomoles of 4a blocked only 30% of the specific binding of [18F]4d, while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [18F]4b and [18F]4c showed lower specific binding ratios than [carbonyl-11C]4a and [18F]4d. [18F]4c was superior to [18F]4b since its specific binding was more readily blocked by 4a. These studies suggest that [18F]4c should be a useful compound to assess dynamic changes in serotonin levels while [18F]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution.     

Recent advances in the development of amyloid imaging agents

Excessive amyloid-beta (Abeta) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). Therefore, Abeta deposits have enough potential to become a useful biomarker for not only an early diagnosis of AD, but also for the assessment of the clinical efficacy of anti-Abeta therapies, if they can be measured non-invasively and reliably in living patients. As a potent candidate technique to measure this biomarker, PET amyloid imaging using a radioligand for Abeta deposits has received much attention. A large number of Abeta ligands have been synthesized and evaluated as candidates for amyloid imaging agents. These can be classified into six categories of derivatives: Congo-red, Thioflavine T, stilbene, vinylbenzoxazole, DDNP, and miscellaneous. Many of these derivatives exhibit high binding affinities to Abeta fibrils (below 20 nM) and some of them also show excellent brain pharmacokinetic profiles. The concept of amyloid imaging is currently being tested in human PET studies using optimized amyloid imaging agents. Despite the small number of subjects, these studies have demonstrated sufficiently promising results. This review article provides an overview of recent advances in the development of amyloid imaging agents, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Abeta ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging agents (PIB, SB-13, BF-227, and FDDNP).     

Synthesis and preliminary evaluation of 2‐arylhydroxyquinoline derivatives for tau imaging

Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of β‐amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2‐arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [¹⁸F]THK‐523. THK‐951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (K_i = 20.7 nM); thus, we radiosynthesized a ¹¹C‐labeled THK‐951 and further studied its potential as a tau PET probe. The [¹¹C]THK‐951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [¹¹C]THK‐951 for in vivo PET imaging of tau pathology in AD. Copyright © 2013 John Wiley & Sons, Ltd.