4-(6-iodo-2-imidazo[1-2-a]pyridinyl)-N-N-dimethylaniline and Alzheimer-Disease

A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Aβ plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Aβ fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Aβ aggregates (Ki = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Benzene Derivatives; Brain; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Molecular Docking Simulation; Molecular Probes; Molecular Structure; Plaque, Amyloid; Positron-Emission Tomography

Benzyloxybenzene, as a novel flexible scaffold without rigid planarity, was synthesized and evaluated as ligand toward Aβ plaques. The binding site calculated for these flexible ligands was the hydrophobic Val18_Phe20 channel on the flat surface of Aβ fiber. Structure-activity relationship analysis generated a common trend that binding affinities declined significantly from para-substituted ligands to ortho-substituted ones, which was also quantitatively illustrated by 3D-QSAR modeling. Autoradiography in vitro further confirmed the high affinities of radioiodinated ligands [125I]4, [125I]24, and [125I]22 (Ki=24.3, 49.4, and 17.6 nM, respectively). In biodistribution, [125I]4 exhibited high initial uptake and rapid washout property in the brain with brain2 min/brain60 min ratio of 16.3. The excellent in vitro and in vivo biostability of [125I]4 enhanced its potential for clinical application in SPECT imaging of Aβ plaques. This approach could also allow the design of a new generation of Aβ targeting ligands without rigid and planar framework.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Female; Humans; Iodine Radioisotopes; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Middle Aged; Molecular Docking Simulation; Molecular Structure; Phenyl Ethers; Plaque, Amyloid; Quantitative Structure-Activity Relationship; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

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 K(i) value ranging from 6 to 326 nM. 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, [(125)I]1 displayed moderate uptake (1.55%ID/g at 2 min) and clearance from the brain with time (0.76 ID/g at 60 min). Taken together, DPP can serve as a new molecular scaffold for developing novel Aβ imaging agents by introducing appropriate substituted groups.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Chalcone; Contrast Media; Humans; Mice; Mice, Transgenic; Molecular Probes; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography

A series of chaclone derivatives containing an indole moiety were evaluated in competitive binding assays with Aβ(1-42) aggregates versus [(125)I]IMPY. The affinity of these compounds ranged from 4.46 to >1008 nM, depending on the substitution on the phenyl ring. Fluorescent staining in vitro showed that one compound with a N,N-dimethylamino group intensely stained Aβ plaques within brain sections of AD transgenic mice. The radioiodinated probe [(125)I]-(E)-3-(1H-indol-5-yl)-1-(4-iodophenyl)prop-2-en-1-one, [(125)I]4, was prepared and autoradiography in sections of brain tissue from an animal model of AD showed that it labeled Aβ plaques specifically. However, experiments with normal mice indicated that [(125)I]4 exhibited a low uptake into the brain in vivo (0.41% ID/g at 2 min). Additional chemical modifications of this indole-chalcone structure may lead to more useful imaging agents for detecting β-amyloid plaques in the brains of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Chalcone; Fluorescent Dyes; Indoles; Iodine Radioisotopes; Mice; Mice, Transgenic; Microscopy, Fluorescence; Peptide Fragments; Pyrazoles; Radionuclide Imaging; Tissue Distribution

We designed and synthesized a small series of 2-aryl-imidazo[2,1-b]benzothiazole, representing a combination of motifs from the two most potent amyloid imaging agents, PIB and IMPY. The binding affinity of the new compounds ranged from 6 to 133 nM. Among the best compounds, 3b (K(i)=6 nM) can be labeled with (11)CH(3) for PET imaging whereas 3j (K(i)=10.9 nM) can be labeled with (123)I for SPECT imaging.

Topics: Alzheimer Disease; Amyloid; Benzothiazoles; Binding, Competitive; Biological Assay; Humans; Imidazoles; Positron-Emission Tomography; Protein Binding; Tomography, Emission-Computed, Single-Photon

A series of benzofuran-2-yl(phenyl)methanone derivatives were synthesized and evaluated as novel probes for β-amyloid plaques. These derivatives were produced by a Rap-Stoermer condensation reaction. Compounds with a N,N-dimethylamino group displayed high affinity for Aβ(1-42) aggregates with K(i) values in the nanomolar range. Autoradiography with brain sections of AD model mice (APP/PS1) revealed that a radioiodinated probe, [(125)I]10, labeled β-amyloid plaques selectively and displayed good brain uptake (3.53% ID/g) at 2 min. The results suggest that benzofuran-2-yl(phenyl)methanone derivatives should be investigated further as potential probes for detecting β-amyloid plaques in the AD brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Autoradiography; Benzofurans; Brain; Iodine Radioisotopes; Ligands; Mice; Peptide Fragments; Plaque, Amyloid; Protein Binding; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution

In a search for new probes to detect β-amyloid plaques in the brain of patients with Alzheimer's disease (AD), we have synthesized and evaluated a series of quinoxaline derivatives containing a '6+6-6' ring system. These quinoxaline derivatives showed excellent affinity for Aβ(1-42) aggregates with K(i) values ranging from 2.6 to 10.7nM. Autoradiography with sections of brain tissue from an animal model of AD mice (APP/PS1) and AD patients revealed that [(125)I]5 labeled β-amyloid plaques specifically. In biodistribution experiments using normal mice, [(125)I]5 displayed high uptake (6.03% ID/g at 2min) into and a moderately fast washout from the brain. Although additional refinements are needed to decrease the lipophilicity and improve the washout rate, the quinoxaline scaffold may be useful as a backbone structure to develop novel β-amyloid imaging agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Disease Models, Animal; Humans; Iodine Radioisotopes; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Protein Binding; Quinoxalines; Radiography; Radiopharmaceuticals; Tissue Distribution

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Fluorine Radioisotopes; Humans; Plaque, Amyloid; Positron-Emission Tomography; Pyridines; Stilbenes; Styrenes; Tissue Distribution

A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as beta-amyloid (Abeta) plaque probes. Staining of hippocampus tissue sections from Alzheimer's disease (AD) brain with the representative compound 9 indicated selective labeling of it to Abeta plaques. The binding affinity of radioiodinated [(125)I]9 for AD brain homogenates was 0.21 nM (K(d)), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K(i)>1000 nM). [(125)I]9 possessed the optimal lipophilicity with LogP value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [(123)I]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Humans; Mice; Phthalimides; Tomography, Emission-Computed, Single-Photon

In this study, six novel benzothiazole derivatives based on the bithiophene structure were developed as potential beta-amyloid probes. In vitro binding studies using Abeta aggregates showed that all of them demonstrated high binding affinities with K(i) values ranged from 0.11 to 4.64nM. In vitro fluorescent staining results showed that these compounds can intensely stained Abeta plaques within brain sections of APP/PS1 transgenic mice, animal model for AD. Two radioiodinated compounds [(125)I]-2-(5'-iodo-2,2'-bithiophen-5-yl)-6-methoxybenzo[d]thiazole [(125)I]10 and [(125)I]-2-(2,2'-bithiophen-5-yl)-6-iodobenzo[d]thiazole [(125)I]13 were successfully prepared through an iododestannylation reaction. Furthermore, in vitro autoradiography of the AD model mice brain sections showed that both [(125)I]10 and [(125)I]13 labeled the Abeta plaques specifically with low background. In vivo biodistribution studies in normal mice indicated that [(125)I]13 exhibited high brain uptake (3.42% ID/g at 2min) and rapid clearance from the brain (0.53% ID/g at 60min), while [(125)I]10 showed lower brain uptake (0.87% ID/g at 2min). In conclusion, these preliminary results of this study suggest that the novel radioiodinated benzothiazole derivative [(125)I]13 may be a candidate as an in vivo imaging agent for detecting beta-amyloid plaques in the brain of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Benzothiazoles; Brain; Chromatography, High Pressure Liquid; Female; Injections, Intravenous; Iodine Radioisotopes; Ligands; Mice; Mice, Transgenic; Plaque, Amyloid; Radionuclide Imaging; Radiopharmaceuticals; Solubility; Thiophenes; Tissue Distribution

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.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Chalcones; Drug Design; Female; Fluorine Radioisotopes; Halogenation; Humans; Isotope Labeling; Male; Mice; Polyethylene Glycols; Positron-Emission Tomography; Tissue Distribution

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Carbon Radioisotopes; Humans; Imidazoles; Macaca mulatta; Male; Mice; Positron-Emission Tomography; Pyridines; Radiopharmaceuticals; Rats; Tissue Distribution

A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human Abeta plaques. 6-Ethylthio- (12h), 6-cyano- (12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (15d) analogues were discovered to have high affinity (KI < 10 nM). However, introduction of a hydrophilic thioether group in the 6-position (15a-c, 15e-g) reduced or abolished affinity. In secondary N-methyl analogues, a bromo substituent in the adjacent ring position (14a) imparted high affinity (KI = 7.4 nM) whereas a methyl substituent did not (14c). The tolerance for nonhydrophilic thioether substituents in the 6-position opens up the possibility of developing new sensitive positron emission tomography radioligands for imaging human Abeta plaques in Alzheimer's disease, especially in view of the amenability of thioethers to be labeled with carbon-11 or fluorine-18 through S-alkylation reactions. The structure-activity relationships revealed in this study extends insight into the topography of the binding site for IMPY-like ligands in human Abeta plaques.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Female; Humans; Imidazoles; Iodine; Ligands; Peptide Fragments; Protein Binding; Pyridines; Radioligand Assay; Structure-Activity Relationship

Two new fluorinated imidazo[1,2-a]pyridine derivatives, 6-(2'-fluoroethyl)-2-(4'-dimethylamino)phenylimidazo[1,2-a]pyridine (FEPIP) and 6-(3'-fluoropropyl)-2-(4'-dimethylamino)phenylimidazo[1,2-a]pyridine (FPPIP), were synthesized. The binding affinity for FEPIP and FPPIP to amyloid plaques in human AD cortical tissues was determined. Radiolabeling, in vitro film autoradiography, and micro-PET study were performed with [18F]FPPIP to determine its utility as a radioligand for amyloid plaque imaging in the brain of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Fluorine Radioisotopes; Humans; Macaca mulatta; Molecular Structure; Pyridines

We report a series of p-hydroxy-, p-amino-, p-monomethylamino-, and p-monofluoroethylamino-substituted biphenyltrienes that displayed high binding affinities to beta-amyloid plaques. In an in vitro binding assay using postmortem brain homogenates of Alzheimer's patients and [(125)I]9, the triene compounds showed excellent binding affinities. When labeled with suitable radionuclides, they are useful as in vivo imaging agents for detecting Abeta plaques in the brains of Alzheimer's patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Ligands; Molecular Probes; Molecular Structure; Plaque, Amyloid

A series of novel beta-amyloid (A beta) aggregate-specific ligands, 2-(4'-dimethylaminophenyl)-6-iodoimidazo[1,2-a]pyridine, 16(IMPY), and its related derivatives were prepared. An in vitro binding study with preformed A beta aggregates showed that 16(IMPY) and its bromo derivative competed with binding of 2-(4'-dimethylaminophenyl)-6-iodobenzothiazole, [125I]7(TZDM), a known ligand for A beta aggregates, with high binding affinities (K(i) = 15 and 10 nM, respectively). In vitro autoradiography of brain sections of a transgenic mouse (Tg2576) with [125I]16(IMPY) displayed high selective binding to amyloid-like structures, comparable to that observed by staining with thioflavin-S visualized under fluorescence. In vivo biodistribution after an intravenous injection of [125I]16(IMPY) in normal mice showed a high initial brain uptake and fast washout, indicating a low background activity associated with this iodinated ligand. Taken together, the data suggests that [123I]16(IMPY) may be useful for imaging A beta aggregates in patients with Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Imidazoles; In Vitro Techniques; Iodine Radioisotopes; Ligands; Male; Mice; Mice, Inbred ICR; Pyridines; Radiopharmaceuticals; Structure-Activity Relationship