Imaging Of Β-amyloid Plaques Research Articles

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.

Diphenylpropynone derivatives as probes for imaging β-amyloid plaques in Alzheimer’s brains

A new series of diphenylpropynone (DPP) derivatives for use in vivo to image β-amyloid (Aβ) plaques in the brain of patients with Alzheimer’s disease (AD) were synthesized and characterized. Binding experiments in vitro revealed high affinity for Aβ (1–42) aggregates at a Ki value ranging from 6 to 326nM. Furthermore, specific labeling of plaques was observed in sections of brain tissue from Tg2576 transgenic mice stained using one of the compounds, 1. In biodistribution experiments with normal mice, [125I]1 displayed moderate uptake (1.55%ID/g at 2min) and clearance from the brain with time (0.76ID/g at 60min). Taken together, DPP can serve as a new molecular scaffold for developing novel Aβ imaging agents by introducing appropriate substituted groups.

A novel 18F-labeled pyridyl benzofuran derivative for imaging of β-amyloid plaques in Alzheimer’s brains

A potential probe for PET targeting β-amyloid plaques in Alzheimer’s disease (AD) brain, FPYBF-1 (5-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)- N, N-dimethylpyridin-2-amine), was synthesized and evaluated. In experiments in vitro, FPYBF-1 displayed high affinity for Aβ(1–42) aggregates ( K i = 0.9 nM), and substantial labeling of β-amyloid plaques in sections of postmortem AD brains but not control brains. In experiments in vivo, [ 18F]FPYBF-1 displayed good initial uptake (5.16%ID/g at 2 min postinjection) and rapid washout from the brain (2.44%ID/g at 60 min postinjection) in normal mice, and excellent binding to β-amyloid plaques in a murine model of AD. Furthermore, the specific labeling of plaques labeling was observed in autoradiographs of autopsied AD brain sections. [ 18F]FPYBF-1 may be a useful probe for imaging β-amyloid plaques in living brain tissue.

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Two 99mTc/Re complexes based on flavone and aurone were tested as potential probes for imaging β-amyloid plaques using single photon emission computed tomography. Both 99mTc-labeled derivatives showed higher affinity for Aβ(1–42) aggregates than did 99mTc-BAT. In sections of brain tissue from an animal model of AD, the Re-flavone derivative 9 and Re-aurone derivative 19 intensely stained β-amyloid plaques. In biodistribution experiments using normal mice, 99mTc-labeled flavone and aurone displayed similar radioactivity pharmacokinetics. With additional modifications to improve their brain uptake, 99mTc complexes based on the flavone or aurone scaffold may serve as probes for imaging cerebral β-amyloid plaques.

Novel Benzofurans with (99m)Tc Complexes as Probes for Imaging Cerebral β-Amyloid Plaques.

Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an animal model of AD, (99m)Tc-BAT-BF clearly labeled β-amyloid plaques. In biodistribution experiments using normal mice, (99m)Tc-BAT-BF displayed high uptake soon after its injection and washed out from the brain rapidly, a highly desirable feature for an imaging agent. (99m)Tc-BAT-BF may be a potential probe for imaging β-amyloid plaques in Alzheimer's brains.

Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains.

A series of fluorinated benzofuran derivatives as potential tracers for positron emission tomography (PET) targeting β-amyloid plaques in the brains of patients with Alzheimer's disease (AD) were synthesized and evaluated. The derivatives were produced using an intramolecular Wittig reaction. In experiments in vitro, all displayed high affinity for Aβ(1-42) aggregates with K i values in the nanomolar range. Radiofluorinated 17, [(18)F]17, in particular labeled β-amyloid plaques in sections of Tg2576 mouse brain and displayed high uptake (5.66% ID/g) at 10 min postinjection, sufficient for PET imaging. In addition, in vivo β-amyloid plaque labeling can be clearly demonstrated with [(18)F]17 in Tg2576 mice. In conclusion, [(18)F]17 may be useful for detecting β-amyloid plaques in patients with AD.

Synthesis and evaluation of novel chalcone derivatives with (99m)Tc/Re complexes as potential probes for detection of β-amyloid plaques.

Four (99m)Tc-labeled chalcone derivatives and their corresponding rhenium analogues were tested as potential probes for imaging β-amyloid plaques. The chalcones showed higher affinity for Aβ(1-42) aggregates than did (99m)Tc complexes. In sections of brain tissue from an animal model of AD, the four Re chalcones intensely stained β-amyloid plaques. In biodistribution experiments using normal mice, (99m)Tc-BAT-chalcone ([(99m)Tc]17) displayed high uptake in the brain (1.48% ID/g) at 2 min postinjection. The radioactivity washed out from the brain rapidly (0.17% ID/g at 60 min), a highly desirable feature for an imaging agent. [(99m)Tc]17 may be a potential probe for imaging β-amyloid plaques in Alzheimer's brains.

Synthesis and characterization of novel phenylindoles as potential probes for imaging of β-amyloid plaques in the brain

We synthesized a novel series of phenylindole (PI) derivatives and evaluated their biological activities as probes for imaging Aβ plaques in vivo. The affinity for Aβ plaques was assessed by an in vitro-binding assay using pre-formed synthetic Aβ aggregates. 2-Phenyl-1 H-indole (2-PI) derivatives showed high affinity for Aβ42 aggregates with K i values ranging from 4 to 32 nM. 2-PI derivatives clearly stained Aβ plaques in an animal model of AD. In biodistribution experiments using normal mice, 2-PI derivatives displayed sufficient uptake for imaging, ranging from 1.1% to 2.6% ID/g. Although additional modifications are necessary to improve uptake by and clearance from the brain, 2-PI derivatives may be useful as a backbone structure to develop novel Aβ imaging agents.

Fluoro-pegylated Chalcones as Positron Emission Tomography Probes for in Vivo Imaging of β-Amyloid Plaques in Alzheimer’s Disease

This paper describes the synthesis and biological evaluation of fluoro-pegylated (FPEG) chalcones for the imaging of beta-amyloid (Abeta) plaques in patients with Alzheimer's disease (AD). FPEG chalcone derivatives were prepared by the aldol condensation reaction. In binding experiments conducted in vitro using Abeta(1-42) aggregates, the FPEG chalcone derivatives having a dimethylamino group showed higher Ki values (20-50 nM) than those having a monomethylamino or a primary amine group. When the biodistribution of 11C-labeled FPEG chalcone derivatives having a dimethyamino group was examined in normal mice, all four derivatives were found to display sufficient uptake for imaging Abeta plaques in the brain. 18F-labeled 7c also showed good uptake by and clearance from the brain, although a slight difference between the 11C and 18F tracers was observed. When the labeling of Abeta plaques was carried out using brain sections of AD model mice and an AD patient, the FPEG chalcone derivative 7c intensely labeled Abeta plaques. Taken together, the results suggest 7c to be a useful candidate PET tracer for detecting Abeta plaques in the brain of patients with AD.

18F-Labeled benzylideneaniline derivatives as new ligands for β-amyloid plaque imaging in Alzheimer's disease

Noninvasive early detection of beta-amyloid (Abeta) plaques might be useful for the treatment of patients with Alzheimer's disease (AD). We herein describe the synthesis of (18)F-labeled benzylideneaniline derivatives using a novel labeling approach for imaging Abeta plaques in AD patients. Benzylidenaniline derivatives were synthesized by reacting fluorobenzaldehyde and corresponding aniline derivatives. Fluorobenzaldehyde was labeled with (18)F by incubating [(18)F]fluoride with N,N,N-trimethylbenzaldehyde in the presence of tetrabutylammonium bicarbonate. In vitro binding assay, stability test and biodistribution study were performed. These compounds were stable at alkaline pH (pH >9); however, they were hydrolyzed rapidly at physiological pH (pH approximately 7.4). The K(i) values of amine-containing benzylideneaniline derivatives for Abeta(1-40) and Abeta(1-42) aggregates were 26-78 nM. These (18)F-labeled benzylideneaniline derivatives showed high brain uptake and rapid clearance after intravenous administration in normal mice (1.8-3.1%ID/g at 2 min and 0.1-1.2%ID/g at 30 min). The low level of bone activity at 30 min indicated that these (18)F-labeled benzylideneanilines are not prone to defluorination. Furthermore, the compounds have suitable lipophilicity - a property required to penetrate the blood-brain barrier. These results showed that the instability of these compounds could cause a higher early phase/late phase ratio due to rapid clearance in the normal brain. The findings from this study suggest that these (18)F-labeled benzylideneaniline derivatives are feasible for the imaging of Abeta plaques.

18F-labeled flavones for in vivo imaging of β-amyloid plaques in Alzheimer’s brains

In vivo imaging of β-amyloid (Aβ) aggregates in the brain may lead to early detection of Alzheimer’s disease (AD) and monitoring of the progression and effectiveness of treatment. The purpose of this study was to develop novel 18F-labeled amyloid-imaging probes based on flavones as a core structure. Fluoropegylated (FPEG) flavone derivatives were designed and synthesized. The affinity of the derivatives for Aβ aggregates varied from 5 to 321 nM. In brain sections of AD model mice, FPEG flavones with the dimethylamino group intensely stained β-amyloid plaques. In biodistrubution experiments using normal mice, they displayed high uptake in the brain ranging from 2.9 to 4.2%ID/g at 2 min postinjection. The radioactivity washed out from the brain rapidly (1.3–2.0%ID/g at 30 min), which is highly desirable for β-amyloid imaging agents. FPEG flavones may be potential PET imaging agents for β-amyloid plaques in Alzheimer’s brains.

Development of Positron-Emission Tomography/Single-Photon Emission Computed Tomography Imaging Probes for in Vivo Detection of .BETA.-Amyloid Plaques in Alzheimer's Brains

Currently, the development of radiotracers for in vivo imaging of beta-amyloid plaques in Alzheimer's disease (AD) brains is an important, active area of molecular imaging. Postmortem brains of AD patients reveal neuropathologic features: the presence of beta-amyloid plaques and neurofibrillary tangles, which contain beta-amyloid peptides and highly phosphorylated tau proteins. Increases in the concentration of beta-amyloid in the course of the disease lead to changes in AD brains. Thus, when used in combination with positron-emission tomography/single-photon emission computed tomography (PET/SPECT), beta-amyloid imaging agents could serve as surrogate markers for the early diagnosis and neuropathogenetic studies of AD. Furthermore, quantitative evaluation of beta-amyloid plaques in the brain could facilitate the evaluation of the efficacy of antiamyloid therapies that are currently being investigated. This paper reviews our research on the development of PET/SPECT imaging agents for in vivo detection of beta-amyloid plaques in Alzheimer's brains.

Novel Radioiodinated Aurones as Probes for SPECT Imaging of β-Amyloid Plaques in the Brain

We report a novel series of radioiodinated aurone derivatives as probes for imaging Abeta plaques in the brains of patients with Alzheimer's disease (AD) using single photon emission computed tomography (SPECT). In binding experiments in vitro, aurone derivatives showed very good affinity for Abeta aggregates (K(i) = 1.1 to 3.4 nM). No-carrier-added radioiodinated aurones were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives. In biodistribution experiments using normal mice, aurone derivatives displayed high brain uptake (1.7-4.5% ID/g at 2 min) and rapid clearance from the brain (0.1-0.4% ID/g at 30 min), especially [125I]15. Furthermore, a specific plaque labeling signal was observed in in vitro autoradiography of postmortem AD brain sections using [125I]15. [125I]15 may be a useful SPECT imaging agent for detecting Abeta plaques in the brain of AD.

Evaluation of 18F-FBM for imaging β-amyloid plaques and neurofibrillary tangles

Evaluation of 18F-FBM for imaging β-amyloid plaques and neurofibrillary tangles

Synthesis and Evaluation of N-Methyl and S-Methyl 11C-Labeled 6-Methylthio-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as Radioligands for Imaging β-Amyloid Plaques in Alzheimer’s Disease

6-Thiolato-substituted 2-(4'- N,N-dimethylamino)phenylimidazo[1,2- a]pyridines ( RS-IMPYs; 1- 4) were synthesized as candidates for labeling with carbon-11 ( t 1/2 = 20.4 min) and imaging of A beta plaques in living human brain using positron emission tomography (PET). K i values for binding of these ligands to Alzheimer's disease brain homogenates were measured in vitro against tritium-labeled 6 (Pittsburgh compound B). MeS-IMPY ( 3, K i = 7.93 nM) was labeled with carbon-11 at its S- or N-methyl position to give [ (11)C] 7 or [ (11)C] 8, respectively. After injection into rats, [ (11)C] 7 or [ (11)C] 8 gave moderately high brain uptakes of radioactivity followed by rapid washout to low levels. The ratio of radioactivity at maximal uptake to that at 60 min reached 18.7 for [ (11)C] 7. [ (11)C] 7 behaved similarly in mouse and monkey. [ (11)C] 7 also bound selectively to A beta plaques in post mortem human Alzheimer's disease brain. Although rapidly metabolized in rat by N-demethylation, [ (11)C] 7 was stable in rat brain homogenates. The ex vivo brain radiometabolites observed in rats have a peripheral origin. Overall, [ (11)C] 7 merits further evaluation in human subjects.

Novel chalcones as probes for in vivo imaging of β-amyloid plaques in Alzheimer’s brains

A novel series of chalcone derivatives for in vivo imaging β-amyloid plaques in the brain of Alzheimer’s disease (AD) were synthesized and characterized. When in vitro binding studies using Aβ aggregates were carried out with chalcone derivatives, the binding affinities for Aβ aggregate varied from 3 to 105 nM. The radioiodinated chalcones were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives using hydrogen peroxide as the oxidant in high yields and with high radiochemical purities. Biodistribution studies in normal mice after iv injection of the radioiodinated chalcones displayed high brain uptake (2.0–4.7%ID/g at 2 min) and rapid clearance from the brain (0.2–0.6%ID/g at 30 min), which is highly desirable for amyloid imaging agents. The results in this study suggest that the novel radioiodinated chalcones may be useful amyloid imaging agents for detecting β-amyloid plaques in the brain of AD.

Brain and whole-body imaging in nonhuman primates with [11C]MeS-IMPY, a candidate radioligand for β-amyloid plaques

[(11)C]MeS-IMPY ([S-methyl-(11)C]N,N-dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline) is a potential radioligand for imaging beta-amyloid plaques with positron emission tomography (PET). The aims of this study were to evaluate [(11)C]MeS-IMPY uptake in nonhuman primate brain and to estimate radiation exposure from serial whole-body images. Eight PET studies were performed in rhesus monkeys to measure the brain uptake and washout of [(11)C]MeS-IMPY. Time-activity data were analyzed with one-tissue and two-tissue compartmental models using radiometabolite-corrected plasma input function. In addition, two whole-body PET scans were acquired for 120 min to determine the biodistribution of [(11)C]MeS-IMPY. Tomographic PET images were compressed into a single planar image to identify organs with the highest radiation exposures. Estimates of the absorbed dose of radiation were calculated using OLINDA 1.0. Injection of [(11)C]MeS-IMPY caused little change in pulse rate, blood pressure, respiratory rate and temperature. [(11)C]MeS-IMPY showed high standardized brain uptake values of approximately 500% and 600% between 2 and 3 min in cortical regions and the cerebellum, respectively. The brain uptake of [(11)C]MeS-IMPY was widespread and quite uniform across all cortical regions. Activity rapidly washed out of the brain, with 20% of peak activity remaining at 40 min. Thus, all brain regions showed minimal retention of radioactivity, consistent with these healthy young animals having negligible amyloid plaques. Regional brain activity fitted well into a one-tissue compartment model. The average volume of distribution in all brain regions was 7.66+/-2.14 ml/cm(3) (n=4). The organs with the highest radiation exposure (muSv/MBq) were the gallbladder wall (33.4), urinary bladder (17) and lungs (12.9), with a resulting effective dose of 4.9 microSv/MBq (18 mrem/mCi). The high brain uptake, rapid washout and quantifiable volume of distribution in nonhuman primate brain further support the evaluation of [(11)C]MeS-IMPY. Calculated dosimetry results are comparable with those for other (11)C-labeled brain imaging radioligands.

Aurones serve as probes of β-amyloid plaques in Alzheimer’s disease

A novel series of aurone derivatives for in vivo imaging of β-amyloid plaques in the brain of Alzheimer’s disease (AD) were synthesized and characterized. When in vitro binding studies using Aβ(1−42) aggregates were carried out with aurone derivatives, they showed high binding affinities for Aβ(1−42) aggregates at the K i values ranging from 1.2 to 6.8 nM. When in vitro plaque labeling was carried out using double transgenic mice brain sections, the aurone derivatives intensely stained β-amyiloid plaques. Biodistribution studies in normal mice after i.v. injection of the radioiodinated aurones displayed high brain uptake (1.9–4.6% ID/g at 2 min) and rapid clearance from the brain (0.11–0.26% ID/g at 60 min), which is highly desirable for amyloid imaging agents. The results in this study suggest that novel radiolabeled aurones may be useful amyloid imaging agents for detecting β-amyloid plaques in the brain of AD.

Curcumin and Dehydrozingerone Derivatives: Synthesis, Radiolabeling, and Evaluation for β-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.

Synthesis and evaluation of benzothiophene derivatives as ligands for imaging β-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.