Co-reporter:Hiroyuki Watanabe, Taisuke Ariyoshi, Akihiko Ozaki, Masafumi Ihara, Masahiro Ono, Hideo Saji
Bioorganic & Medicinal Chemistry 2017 Volume 25, Issue 24(Issue 24) pp:
Publication Date(Web):15 December 2017
DOI:10.1016/j.bmc.2017.10.010
α-Synuclein (α-syn) aggregates are commonly found in the brains of patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and some other diseases. Therefore, in vivo imaging of α-syn aggregates would aid in drug development, early diagnosis, and monitoring of disease status. In order to develop imaging probes targeting α-syn aggregates, we synthesized and evaluated three novel radioiodinated benzimidazole (BI) derivatives for selective imaging of α-syn aggregates. In binding experiments, BI-2 exhibited the highest selective binding affinity for α-syn aggregates among the BI derivatives. In addition, BI-2 clearly stained Lewy bodies in PD brain sections, but did not label senile plaques deposited in AD brain sections. However, in the biodistribution study using normal mice, [125I]BI-2 did not demonstrate high brain uptake (0.56%ID/g at 2-min post-injection). Further structural modifications of the BI derivatives are needed, but the BI scaffold may be an attractive candidate for developing α-syn imaging probes.Download high-res image (72KB)Download full-size image
Co-reporter:Shimpei Iikuni;Keiichi Tanimura;Hiroyuki Watanabe;Masashi Yoshimura;Hideo Saji
RSC Advances (2011-Present) 2017 vol. 7(Issue 33) pp:20582-20590
Publication Date(Web):2017/04/05
DOI:10.1039/C6RA28395K
The development of an imaging probe targeting β-amyloid (Aβ) plaques in Alzheimer's disease labeled with technetium-99m, the most commonly used radioisotope for clinical diagnoses, has been strongly anticipated. In this study, we synthesized three novel 99mTc complexes with the phenylquinoxaline scaffold and evaluated their properties for imaging Aβ plaques. The 99mTc and corresponding Re complexes were synthesized with bis(aminoethanethiol) (BAT) as a chelating ligand. In a binding affinity assay using recombinant Aβ(1–42) aggregates in vitro, the 99mTc-labeled N,N-dimethylated phenylquinoxaline derivative (99mTc-BAT-C3-PQ-1) and the corresponding Re complex showed sufficient affinity for Aβ(1–42) aggregates. An in vivo biodistribution study in normal mice revealed that 99mTc-BAT-C3-PQ-1 showed a moderate initial brain uptake and a reasonable clearance from the brain. An ex vivo autoradiographic examination with 99mTc-BAT-C3-PQ-1 showed the marked labeling of Aβ plaques in brain sections from Tg2576 transgenic mice but not age-matched controls. 99mTc-BAT-C3-PQ-1 may be a potential single photon emission computed tomography probe for imaging Aβ plaques in Alzheimer's disease.
Co-reporter:Masashi Yoshimura, Masahiro Ono, Hiroyuki Watanabe, Hiroyuki Kimura, and Hideo Saji
Bioconjugate Chemistry 2016 Volume 27(Issue 6) pp:1532
Publication Date(Web):May 24, 2016
DOI:10.1021/acs.bioconjchem.6b00174
While islet amyloid deposition comprising amylin is one of pathological hallmarks of type 2 diabetes mellitus (T2DM), no useful amylin-imaging probe has been reported. In this study, we evaluated two 99mTc-labeled pyridyl benzofuran derivatives as novel amylin-imaging probes using the newly established islet amyloid model mouse. Binding experiments in vitro demonstrated that [99mTc]1 displayed a higher affinity for amylin aggregates than [99mTc]2. Autoradiographic studies using human pancreas sections with T2DM revealed that [99mTc]1 clearly labeled islet amyloid in T2DM pancreatic sections, while [99mTc]2 did not. Although the initial uptake of [99mTc]1 by the normal mouse pancreas was low (0.74%ID/g at 2 min post-injection), [99mTc]1 showed higher retention in the model mouse pancreas than that of the normal mouse, and exhibited strong binding to amylin aggregates in the living pancreas of the model mice. These results suggest that [99mTc]1 is a potential imaging probe targeting islet amyloids in the T2DM pancreas.
Co-reporter:Masahiro Ono, Yuki Doi, Hiroyuki Watanabe, Masafumi Ihara, Akihiko Ozaki and Hideo Saji
RSC Advances 2016 vol. 6(Issue 50) pp:44305-44312
Publication Date(Web):04 May 2016
DOI:10.1039/C6RA02710E
It is generally recognized that aggregates of α-synuclein (α-syn) in the brain are closely associated with the pathogenesis of Parkinson's disease (PD). Therefore, the development of in vivo imaging probes targeting α-syn aggregates is currently expected. In this study, we investigated the structure–activity relationships of radioiodinated diphenyl (IDP) derivatives with different conjugated double bonds as ligands for α-syn aggregates. An in vitro binding assay revealed that the binding affinity of the derivatives to α-syn aggregates increased as the length of the conjugated double bonds in their molecule extended. In contrast, brain uptake of the derivatives in biodistribution studies decreased in accordance with the extension of the double bonds. These findings from structure-relationship studies suggested that the length of the conjugated double bonds in the IDP derivatives plays an important role in the binding affinity for α-syn aggregates and uptake in the brain. Also, the present study may provide valuable information on molecular design for the development of new imaging probes targeting α-syn aggregates in the future.
Co-reporter:Hiroyuki Watanabe, Azusa Kawasaki, Kohei Sano, Masahiro Ono, Hideo Saji
Bioorganic & Medicinal Chemistry 2016 Volume 24(Issue 16) pp:3618-3623
Publication Date(Web):15 August 2016
DOI:10.1016/j.bmc.2016.06.001
In vivo imaging of β-amyloid (Aβ) aggregates consisting of Aβ(1–40) and Aβ(1–42) peptides by positron emission tomography (PET) contributes to the diagnosis and therapy for Alzheimer’s disease (AD). Because 64Cu (t1/2 = 12.7 h) is a radionuclide for PET with a longer physical half-life than 11C (t1/2 = 20 min) and 18F (t1/2 = 110 min), it is an attractive radionuclide for the development of Aβ imaging probes that are suitable for routine use. In the present study, we designed and synthesized two novel 64Cu labeled benzofuran derivatives and evaluated their utility as PET imaging probes for Aβ aggregates. In an in vitro binding assay, 6 and 8 showed binding affinity for Aβ(1–42) aggregates with a Ki value of 33 and 243 nM, respectively. In addition, these probes bound to Aβ plaques deposited in the brain of an AD model mouse in vitro. In a biodistribution experiment using normal mice, these probes showed low brain uptake (0.33% and 0.36% ID/g) at 2 min post-injection. Although refinement to enhance brain uptake is needed, [64Cu]6 and [64Cu]8 demonstrated the feasibility of developing novel PET probes for imaging Aβ aggregates.
Co-reporter:Masahiro Ono;Ayane Kitada;Hiroyuki Watanabe;Anna Miyazaki;Hiroyuki Kimura ;Hideo Saji
Journal of Labelled Compounds and Radiopharmaceuticals 2016 Volume 59( Issue 8) pp:317-321
Publication Date(Web):
DOI:10.1002/jlcr.3404
Abstract
We report on the synthesis and preliminary characterization of two radioiodinated benzofuran-3-yl-(indol-3-yl)maleimides, 3-(benzofuran-3-yl)-4-(5-[125I]iodo-1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione ([125I]5), and 3-(5-[125I]iodo-1-methyl-1H-indol-3-yl)-4-(6-methoxybenzofuran-3-yl)-1H-pyrrole-2,5-dione ([125I]6), as the first potential SPECT imaging probes targeting glycogen synthase kinase-3β (GSK-3β). In this study, we used 125I as a surrogate of 123I because of its ease of use. The radioiodinated ligands were prepared from the corresponding tributyltin precursors through an iododestannylation reaction using hydrogen peroxide as an oxidant with a radiochemical yield of 10–30%. In vitro binding experiments suggested that both compounds show high affinity for GSK-3β at a level similar to a known GSK-3β inhibitor. Biodistribution studies with normal mice revealed that the radioiodinated compounds display sufficient uptake into (1.8%ID/g at 10 min postinjection) and clearance from the brain (1.0%ID/g at 60 min postinjection). These preliminary results suggest that the further optimization of radioiodinated benzofuran-3-yl-(indol-3-yl)maleimide derivatives may facilitate the development of clinically useful SPECT imaging probes for the in vivo detection of GSK-3β.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono and Hideo Saji
Chemical Communications 2015 vol. 51(Issue 96) pp:17124-17127
Publication Date(Web):12 Oct 2015
DOI:10.1039/C5CC06628J
In vivo fluorescence imaging of β-amyloid (Aβ) plaques in the brain is expected to be used as a new method for detecting Alzheimer's disease (AD). We synthesized novel push–pull dimethylaminothiophenyl (DTM) derivatives and evaluated their utility as in vivo fluorescence imaging probes targeting Aβ plaques. As a result, we found that DTM-2 is a promising fluorescent probe for Aβ plaques in the AD brains.
Co-reporter:Kenji Matsumura; Masahiro Ono; Ayane Kitada; Hiroyuki Watanabe; Masashi Yoshimura; Shimpei Iikuni; Hiroyuki Kimura; Yoko Okamoto; Masafumi Ihara;Hideo Saji
Journal of Medicinal Chemistry 2015 Volume 58(Issue 18) pp:7241-7257
Publication Date(Web):September 1, 2015
DOI:10.1021/acs.jmedchem.5b00440
In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer’s disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([125I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [125I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [123I]64 may be a new candidate tau-imaging agent.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Shimpei Iikuni, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara and Hideo Saji
RSC Advances 2015 vol. 5(Issue 2) pp:1009-1015
Publication Date(Web):01 Dec 2014
DOI:10.1039/C4RA10742J
In vivo imaging of β-amyloid (Aβ) plaques by non-invasive techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) may facilitate early diagnosis and drug discovery for the treatment of Alzheimer's disease (AD). SPECT is known as a more useful modality than PET in terms of routine diagnostic use, but there have been no reports on attractive probes in clinical studies. In this study, we synthesized and evaluated novel 123I-labeled pyridyl benzoxazole (PBOX) derivatives as SPECT probes for imaging Aβ plaques in vivo. The PBOX derivatives showed affinity for Aβ(1–42) aggregates in vitro (Ki = 6.9–138 nM). In biodistibution experiments in normal mice, all these derivatives showed high initial uptake into (4.6–6.6% ID g−1 at 2 min) and rapid clearance (0.3–1.3% ID g−1 at 60 min) from the brain. Furthermore, [125I]9 clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD brain sections. SPECT/CT study with [123I]9 displayed higher radioactivity in Tg2576 mice than wild-type mice. In addition, ex vivo autoradiograms of brain sections from Tg2576 mice after the injection of [123I]9 showed selective binding of Aβ plaques. In conclusion, [123I]9 may be a potential SPECT probe for imaging Aβ plaques in AD brain.
Co-reporter:Masahiro Ono and Hideo Saji
MedChemComm 2015 vol. 6(Issue 3) pp:391-402
Publication Date(Web):25 Nov 2014
DOI:10.1039/C4MD00365A
In this review, we introduce recent advances in our development of molecular imaging probes for positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging for the detection of β-amyloid plaques in the brains of patients with Alzheimer's disease.
Co-reporter:Mengchao Cui ; Masahiro Ono ; Hiroyuki Watanabe ; Hiroyuki Kimura ; Boli Liu ;Hideo Saji
Journal of the American Chemical Society 2014 Volume 136(Issue 9) pp:3388-3394
Publication Date(Web):February 20, 2014
DOI:10.1021/ja4052922
The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer’s disease (AD); however, early detection of AD still presents a challenge. With the assistance of molecular imaging techniques, imaging agents specifically targeting Aβ plaques in the brain may lead to the early diagnosis of AD. Herein, we report the design, synthesis, and evaluation of a series of smart near-infrared fluorescence (NIRF) imaging probes with donor–acceptor architecture bridged by a conjugated π-electron chain for Aβ plaques. The chemical structure of these NIRF probes is completely different from Congo Red and Thioflavin-T. Probes with a longer conjugated π system (carbon–carbon double bond) displayed maximum emission in PBS (>650 nm), which falls in the best range for NIRF probes. These probes were proved to have affinity to Aβ plaques in fluorescent staining of brain sections from an AD patient and double transgenic mice, as well as in an in vitro binding assay using Aβ1–42 aggregates. One probe with high affinity (Ki = 37 nM, Kd = 27 nM) was selected for in vivo imaging. It can penetrate the blood–brain barrier of nude mice efficiently and is quickly washed out of the normal brain. Moreover, after intravenous injection of this probe, 22-month-old APPswe/PSEN1 mice exhibited a higher relative signal than control mice over the same period of time, and ex vivo fluorescent observations confirmed the existence of Aβ plaques. In summary, this probe meets most of the requirements for a NIRF contrast agent for the detection of Aβ plaques both in vitro and in vivo.
Co-reporter:Shimpei Iikuni, Masahiro Ono, Hiroyuki Watanabe, Kenji Matsumura, Masashi Yoshimura, Naoya Harada, Hiroyuki Kimura, Morio Nakayama, and Hideo Saji
Molecular Pharmaceutics 2014 Volume 11(Issue 4) pp:1132-1139
Publication Date(Web):March 27, 2014
DOI:10.1021/mp400499y
Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel 99mTc-hydroxamamide (99mTc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1–42)) aggregates as a model. In vitro inhibition assay indicated that bivalent 99mTc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent 99mTc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent 99mTc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.Keywords: amyloid aggregates; amyloidosis; imaging; multivalent interactions; technetium-99m;
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Shimpei Iikuni, Masashi Yoshimura, Kenji Matsumura, Hiroyuki Kimura, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 20) pp:4834-4837
Publication Date(Web):15 October 2014
DOI:10.1016/j.bmcl.2014.08.058
Since the imaging of β-amyloid (Aβ) plaques in the brain is believed to be a useful tool for the early diagnosis of Alzheimer’s disease (AD), a number of imaging probes to detect Aβ plaques have been developed. Because the radionuclide 68Ga (t1/2 = 68 min) for PET imaging could become an attractive alternative to 11C and 18F, we designed and synthesized a benzofuran derivative conjugated with a 68Ga complex (68Ga-DOTA-C3-BF) as a novel Aβ imaging probe. In an in vitro binding assay, Ga-DOTA-C3-BF showed high affinity for Aβ(1-42) aggregates (Ki = 10.8 nM). The Ga-DOTA-C3-BF clearly stained Aβ plaques in a section of Tg2576 mouse, reflecting the affinity for Aβ(1-42) aggregates in vitro. In a biodistribution study in normal mice, 68Ga-DOTA-C3-BF displayed low initial uptake (0.45% ID/g) in the brain at 2 min post-injection. While improvement of the brain uptake of 68Ga complexes appears to be essential, these results suggest that novel PET imaging probes that include 68Ga as the radionuclide for PET may be feasible.This Letter describes a 68Ga complex based on benzofuran scaffold for the detection of β-amyloid plaques.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Hiroyuki Kimura, Kenji Matsumura, Masashi Yoshimura, Shimpei Iikuni, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi and Hideo Saji
MedChemComm 2014 vol. 5(Issue 1) pp:82-85
Publication Date(Web):10 Dec 2013
DOI:10.1039/C3MD00189J
We designed and synthesized a novel series of radioiodinated 3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine (1,3,4-PODP) derivatives for imaging β-amyloid (Aβ) plaques in Alzheimer's disease (AD) brains using single photon emission computed tomography (SPECT). In binding experiments in vitro, 1,3,4-PODP derivatives (3 and 6) displayed high affinity for Aβ(1-42) aggregates (25 and 14 nM, respectively). In experiments in vivo, [123/125I]3 and [123/125I]6 displayed good initial uptake into and rapid washout from the brain in normal mice, and clearly labeled Aβ plaques in Tg2576 mice. Furthermore, specific labeling of Aβ plaques was observed in in vitro autoradiography of postmortem AD brain sections. These results suggested that 1,3,4-PODP derivatives may be useful SPECT probes for detecting Aβ plaques in AD brains.
Co-reporter:Masashi Yoshimura, Masahiro Ono, Kenji Matsumura, Hiroyuki Watanabe, Hiroyuki Kimura, Mengchao Cui, Yuji Nakamoto, Kaori Togashi, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, and Hideo Saji
ACS Medicinal Chemistry Letters 2013 Volume 4(Issue 7) pp:596-600
Publication Date(Web):May 21, 2013
DOI:10.1021/ml4000707
This letter describes the synthesis, structure–activity relationships, and in vivo evaluation of a new series of 2-phenylquinoxaline (PQ) derivatives for imaging β-amyloid (Aβ) plaques in Alzheimer’s disease (AD). In experiments in vitro, the affinity of the derivatives for Aβ aggregates varied, with Ki values of 0.895 to 1180 nM. In brain sections from AD patients, derivatives with a Ki of less than 111 nM intensely labeled Aβ plaques, while those with values over 242 nM showed no marked labeling. In biodistribution experiments using normal mice, the derivatives showed good uptake into (4.69–7.59 %ID/g at 2 or 10 min postinjection) and subsequent washout from (1.48–3.08 %ID/g at 60 min postinjection) the brain. In addition, [18F]PQ-6 labeled Aβ plaques in vivo in APP transgenic mice, while it showed nonspecific binding in the white matter. Further structural optimization based on [18F]PQ-6 may lead to more useful PET probes for imaging Aβ plaques.Keywords: Alzheimer’s disease (AD); PET; quinoxaline; structure−activity relationships; β-amyloid (Aβ);
Co-reporter:Kenji Matsumura, Masahiro Ono, Masashi Yoshimura, Hiroyuki Kimura, Hiroyuki Watanabe, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hideo Saji
Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 11) pp:3356-3362
Publication Date(Web):1 June 2013
DOI:10.1016/j.bmc.2013.02.054
This paper describes the synthesis and biological evaluation of styrylbenzimidazole (SBIM) derivatives as agents for imaging neurofibrillary tangles (NFT) in patients with Alzheimer’s disease (AD). SBIM derivatives were prepared with 4-iodobenzene-1,2-diamine and substituted cinnamaldehydes. In binding experiments using recombinant tau and Aβ1–42 aggregates, SBIM-3 showed higher affinity for the tau aggregates than Aβ1–42 aggregates (ratio of Kd values was 2.73). In in vitro autoradiography and fluorescent staining, [125I]SBIM-3 (or SBIM-3) bound NFT in sections of AD brain tissue. In biodistribution experiments using normal mice, all [125I]SBIM derivatives showed high initial uptake into (3.20–4.11%ID/g at 2 min after the injection) and rapid clearance from (0.12–0.33%ID/g at 60 min after the injection) the brain. In conclusion, appropriate structural modifications of SBIM derivatives could lead to more useful agents for the in vivo imaging of NFT in AD brains.
Co-reporter:Yan Cheng ; Masahiro Ono ; Hiroyuki Kimura ; Masashi Ueda ;Hideo Saji
Journal of Medicinal Chemistry 2012 Volume 55(Issue 5) pp:2279-2286
Publication Date(Web):February 24, 2012
DOI:10.1021/jm201513c
Three novel 99mTc-labeled pyridyl benzofuran derivatives were tested as potential probes for imaging β-amyloid plaques using single photon emission computed tomography (SPECT). The 99mTc and corresponding rhenium complexes were synthesized with bis(aminoethanethiol) (BAT) as a chelating ligand. All Re complexes showed affinity for Aβ(1–42) aggregates (Ki = 13.6–149.6 nM). Biodistribution experiments in normal mice revealed that the 99mTc-labeled derivatives displayed sufficient uptake in the brain (1.41–1.80% ID/g at 2 min postinjection). Notably, [99mTc]BAT-Bp-2 showed a good initial uptake (1.80% ID/g at 2 min) and a reasonable washout from the brain (0.79% ID/g at 60 min). Ex vivo autoradiography with [99mTc]BAT-Bp-2 revealed substantial labeling of β-amyloid plaques in sections of brain tissue from Tg2576 transgenic mice but not in the age-matched controls. [99mTc]BAT-Bp-2 may be a potential SPECT probe for imaging β-amyloid plaques in Alzheimer’s brains.
Co-reporter:Mengchao Cui ; Masahiro Ono ; Hiroyuki Kimura ; Masashi Ueda ; Yuji Nakamoto ; Kaori Togashi ; Yoko Okamoto ; Masafumi Ihara ; Ryosuke Takahashi ; Boli Liu ;Hideo Saji
Journal of Medicinal Chemistry 2012 Volume 55(Issue 21) pp:9136-9145
Publication Date(Web):June 12, 2012
DOI:10.1021/jm300251n
Two radiofluoro-pegylated phenylbenzoxazole derivatives, 4-(5-(2-(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N-methylaniline ([18F]24) and 4-(5-(2-(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N,N-dimethylaniline ([18F]32), were synthesized and evaluated as probes for imaging cerebral β-amyloid (Aβ) plaques in living brain tissue by PET. [18F]24 and [18F]32 displayed high affinity for Aβ1–42 aggregates (Ki = 9.3 and 3.9 nM, respectively). In vitro autoradiography with sections of post-mortem AD brain and transgenic mouse brain confirmed the affinity of these tracers. Initial high uptake into and rapid washout from the brain in normal mice were observed. [18F]24 also displayed excellent binding to Aβ plaques in ex vivo autoradiographic experiments with Tg2576 mice. Furthermore, small-animal PET studies demonstrated significant differences in the clearance profile after the administration of [18F]24 between Tg2576 and wild-type mice. The results suggest [18F]24 to be a useful PET agent for detecting Aβ plaques in the living human brain.
Co-reporter:Masahiro Ono, Hiroyuki Watanabe, Hiroyuki Kimura, and Hideo Saji
ACS Chemical Neuroscience 2012 Volume 3(Issue 4) pp:319
Publication Date(Web):February 17, 2012
DOI:10.1021/cn3000058
We designed and synthesized a BODIPY-based probe (BAP-1) for the imaging of β-amyloid plaques in the brain. In binding experiments in vitro, BAP-1 showed excellent affinity for synthetic Aβ aggregates. β-Amyloid plaques in Tg2576 mouse brain were clearly visualized with BAP-1. In addition, the labeling of β-amyloid plaques was demonstrated in vivo in Tg2576 mice. These results suggest BAP-1 to be a useful fluorescent probe for the optical imaging of cerebral β-amyloid plaques in patients with Alzheimer’s disease.Keywords: Alzheimer’s disease; BODIPY; optical imaging; β-amyloid plaque
Co-reporter:Kenji Matsumura, Masahiro Ono, Hiroyuki Kimura, Masashi Ueda, Yuji Nakamoto, Kaori Togashi, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, and Hideo Saji
ACS Medicinal Chemistry Letters 2012 Volume 3(Issue 1) pp:58
Publication Date(Web):December 1, 2011
DOI:10.1021/ml200230e
We synthesized and evaluated (E)-4-((6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)diazenyl)-N,N-dimethylaniline (FPPDB) as a probe for the imaging of neurofibrillary tangles (NFTs) in patients with Alzheimer's disease (AD). In assays using thioflavin S (ThS) as a competitive ligand, FPPDB competed with ThS well and showed high affinity for both tau and Aβ1–42 aggregates (Ki = 13.0 and 20.0 nM, respectively). The results of saturation binding assays also verified that FPPDB bound to both tau and Aβ1–42 aggregates with high affinity (Kd = 44.8 nM and Bmax = 45.8 pmol/nmol protein for tau aggregates and Kd = 45.4 nM and Bmax = 38.9 pmol/nmol protein for Aβ1–42 aggregates). Furthermore, [18F]FPPDB substantially labeled NFTs and senile plaques in AD brain sections but not control brain sections. In biodistribution experiments using normal mice, [18F]FPPDB displayed higher uptake (4.28% ID/g at 2 min postinjection) into and washout (2.53% ID/g at 60 min postinjection) from the brain with time. On the basis of the chemical structure of FPPDB, further increases in selective binding to tau aggregates may lead to the development of more useful probes for the imaging of NFTs in AD brains.Keywords: Alzheimer's disease (AD); benzothiazole; imaging; neurofibrillary tangles (NFTs); PET
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Hiroyuki Kimura, Kenji Matsumura, Masashi Yoshimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 17) pp:5700-5703
Publication Date(Web):1 September 2012
DOI:10.1016/j.bmcl.2012.06.086
This letter describes the synthesis and biological evaluation of a novel series of radioiodinated oxindole (OI) derivatives for detecting neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer’s disease (AD). In binding experiments in vitro, 2-oxindole (2-OI) and 3-oxindole (3-OI) derivatives showed affinity for tau aggregates. The 3-OI derivative 14 showed the highest affinity of these derivatives. In biodistribution experiments using normal mice, the OI derivatives displayed good uptake (2.4–2.5% ID/g at 2 min) and clearance from the brain with time (0.6–1.4% ID/g at 30 min). In fluorescence staining experiments using AD brain sections, 14 clearly stained NFTs. 3-OI may serve as a new molecular scaffold for developing novel NFT imaging agents.We report the synthesis and biological evaluation of a novel series of radioiodinated oxindole derivatives for detecting neurofibirillary tangles in the brains of patients with Alzheimer’s disease.
Co-reporter:Masahiro Ono;Masatsugu Ohgami;Mamoru Haratake;Hideo Saji;Morio Nakayama
Journal of Labelled Compounds and Radiopharmaceuticals 2012 Volume 55( Issue 2) pp:71-79
Publication Date(Web):
DOI:10.1002/jlcr.1954
This paper describes the synthesis and biological evaluation of a novel bifunctional chelating agent (BCA) based on bis(hydroxamamide) for 99mTc labeling of polypeptides. We successfully designed and synthesized C3(BHam)2―COOH as a new BCA. C3(BHam)2―COOH formed a stable 99mTc complex and enabled us to prepare 99mTc-labeled polypeptides by using a 2,3,5,6-tetrafluorophenol (TFP) active ester of C3(BHam)2―COOH. 99mTc-C3(BHam)2―HSA prepared with C3(BHam)2―TFP was stable in both murine plasma and an excess of l-cysteine without any dissociation of 99mTc from polypeptides. Furthermore, the blood clearance of 99mTc-C3(BHam)2―HSA in mice was similar to that of 125I-HSA, suggesting that C3(BHam)2―COOH retained stable binding between 99mTc and the polypeptides in vivo. When 99mTc-C3(BHam)2―NGA was injected into mice, the radioactivity showed high hepatic uptake early on and a rapid clearance from the liver, indicating that C3(BHam)2―COOH did not affect the pharmacokinetics of polypeptides in vivo and gave radiometabolites, which displayed a rapid elimination from the liver. Such characteristics would render C3(BHam)2―COOH attractive as a new BCA for 99mTc labeling of polypeptides.
Co-reporter:Mengchao Cui ; Masahiro Ono ; Hiroyuki Kimura ; Boli Liu ;Hideo Saji
Journal of Medicinal Chemistry 2011 Volume 54(Issue 7) pp:2225-2240
Publication Date(Web):March 21, 2011
DOI:10.1021/jm101404k
A new and extensive set of dibenzylideneacetone derivatives was synthesized and screened for affinity toward Aβ1−42 aggregates. Structure−activity relationships revealed the binding of dibenzylideneacetones to be affected by various substituents. The introduction of a substituent group in the ortho position reduced or abolished the binding. However, the para position was highly tolerant of sterically demanding substitutions. Three radioiodinated ligands (6, 70, and 71) and two 18F fluoro-pegylated (FPEG) ligands (83 and 85) were prepared, all of which displayed high affinity for Aβ1−42 aggregates (Ki ranging from 0.9 to 7.0 nM). In biodistribution experiments, they exhibited good initial penetration (1.59, 4.68, 4.56, 4.13, and 5.15% ID/g, respectively, at 2 min) of and fast clearance from the brain. Autoradiography with sections of postmortem AD brain and transgenic mouse brain confirmed the high affinity of these tracers. These preliminary results strongly suggest the dibenzylideneacetone structure to be a potential new scaffold for β-amyloid imaging probes.
Co-reporter:Masahiro Ono ; Yan Cheng ; Hiroyuki Kimura ; Mengchao Cui ; Shinya Kagawa ; Ryuichi Nishii ;Hideo Saji
Journal of Medicinal Chemistry 2011 Volume 54(Issue 8) pp:2971-2979
Publication Date(Web):March 23, 2011
DOI:10.1021/jm200057u
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, [18F]FPYBF-2 ([18F]10) and [18F]FPHBF-2 ([18F]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 (Ki = 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.
Co-reporter:Masahiro Ono, Shun Hayashi, Kenji Matsumura, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hiroshi Mori, and Hideo Saji
ACS Chemical Neuroscience 2011 Volume 2(Issue 5) pp:269
Publication Date(Web):March 21, 2011
DOI:10.1021/cn200002t
A novel series of rhodanin (RH) and thiohydantoin (TH) derivatives were designed and synthesized for detecting tau pathology in the brains of patients with Alzheimer’s disease (AD). In experiments in vitro using tau and β-amyloid (Aβ) aggregates, the TH derivative, TH2, showed high specific binding to tau aggregates. In hippocampal sections obtained from AD patients, TH2 intensely stained neurofibrillary tangles. In experiments using normal mice, [125I]TH2 showed good uptake (1.54%ID/g, 2 min postinjection) into and a rapid washout (0.25%ID/g, 60 min postinjection) from the brain. [123I]TH2 should be further investigated as a potential imaging agent for detecting tau pathology.Keywords: Alzheimer’s disease; imaging; rhodanine; tau; thiohydantoin
Co-reporter:Mengchao Cui, Masahiro Ono, Hiroyuki Kimura, Boli Liu, Hideo Saji
Bioorganic & Medicinal Chemistry 2011 Volume 19(Issue 13) pp:4148-4153
Publication Date(Web):1 July 2011
DOI:10.1016/j.bmc.2011.04.049
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 Aβ1–42 aggregates with Ki values in the nanomolar range. Autoradiography with brain sections of AD model mice (APP/PS1) revealed that a radioiodinated probe, [125I]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.
Co-reporter:Mengchao Cui, Masahiro Ono, Hiroyuki Kimura, Boli Liu, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 14) pp:4193-4196
Publication Date(Web):15 July 2011
DOI:10.1016/j.bmcl.2011.05.079
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 Aβ1–42 aggregates with Ki values ranging from 2.6 to 10.7 nM. Autoradiography with sections of brain tissue from an animal model of AD mice (APP/PS1) and AD patients revealed that [125I]5 labeled β-amyloid plaques specifically. In biodistribution experiments using normal mice, [125I]5 displayed high uptake (6.03% ID/g at 2 min) 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.
Co-reporter:Masahiro Ono, Hiroyuki Watanabe, Rumi Watanabe, Mamoru Haratake, Morio Nakayama, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 1) pp:117-120
Publication Date(Web):1 January 2011
DOI:10.1016/j.bmcl.2010.11.058
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 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, [125I]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.A new series of diphenylpropynone (DPP) derivatives for use in vivo to image β-amyloid plaques in the brain of patients with Alzheimer’s disease were synthesized and characterized.
Co-reporter:Kenji Matsumura, Masahiro Ono, Shun Hayashi, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hiroshi Mori and Hideo Saji
MedChemComm 2011 vol. 2(Issue 7) pp:596-600
Publication Date(Web):26 Apr 2011
DOI:10.1039/C1MD00034A
This paper describes the synthesis and biological evaluation of novel phenyldiazenyl benzothiazole (PDB) derivatives as probes for imaging neurofibrillary tangles (NFTs) in patients with Alzheimer's disease (AD). We successfully synthesized three PDB derivatives using a diazo coupling reaction. In binding experiments in vitro, the compounds displayed higher affinity for tau aggregates than for Aβ aggregates. In fluorescent staining experiments using AD brain sections, 9 visualized NFTs clearly. No-carrier-added radioiodinated PDB derivatives were successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivatives. [125I]9 labeled NFTs in sections of brain tissue from a patient with AD, but not a control. In biodistribution experiments using normal mice, the PDB derivatives displayed an uptake into the brain, sufficient for imaging NFTs, ranging from 0.94 to 3.2% ID g−1, but a relatively slow washout. Although further modifications are necessary to improve the pharmacokinetics in the brain, PDB with high affinity for tau aggregates may be useful as a backbone structure to develop agents for imaging NFTs in AD brains.
Co-reporter:Mengchao Cui, Masahiro Ono, Hiroyuki Kimura, Bo Li Liu, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 3) pp:980-982
Publication Date(Web):1 February 2011
DOI:10.1016/j.bmcl.2010.12.045
A series of chaclone derivatives containing an indole moiety were evaluated in competitive binding assays with Aβ1-42 aggregates versus [125I]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 [125I]-(E)-3-(1H-indol-5-yl)-1-(4-iodophenyl)prop-2-en-1-one, [125I]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 [125I]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.A series of novel indole-chalcone derivatives were synthesized and evaluated as Aβ imaging probes.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Hiroyuki Kimura, Shinya Kagawa, Ryuichi Nishii, Takeshi Fuchigami, Mamoru Haratake, Morio Nakayama, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 21) pp:6519-6522
Publication Date(Web):1 November 2011
DOI:10.1016/j.bmcl.2011.08.063
We report a fluorinated and iodinated radiotracer as a probe for PET/SPECT to detect of β-amyloid (Aβ) plaques in the brain of patients with Alzheimer’s disease (AD). We successfully designed and synthesized the fluorinated and iodinated aurone derivative (3) and its radiolabels ([125I]3 and [18F]3). In binding experiments in vitro, 3 showed high affinity for Aβ aggregates (Ki = 6.81 nM). In brain sections of AD model mice, 3 intensely stained Aβ plaques. Furthermore, a specific plaque labeling signal was observed on the autoradiography of postmortem AD brain sections using [125I]3. In biodistribution experiments using normal mice, [125I]3 and [18F]3 displayed good uptake into and a rapid washout from the brain, properties highly desirable for Aβ imaging agents. These results suggest that 3 may function as a PET/SPECT dual imaging agent for detecting Aβ plaques in AD brains.We report a fluorinated and iodinated radiotracer as a dual imaging probe for PET/SPECT to detect of β-amyloid plaques in the brain of patients with Alzheimer’s disease.
Co-reporter:Masahiro Ono, Ryoichi Ikeoka, Hiroyuki Watanabe, Hiroyuki Kimura, Takeshi Fuchigami, Mamoru Haratake, Hideo Saji, and Morio Nakayama
ACS Chemical Neuroscience 2010 Volume 1(Issue 9) pp:598
Publication Date(Web):July 8, 2010
DOI:10.1021/cn100042d
Four 99mTc-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 99mTc 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, 99mTc-BAT-chalcone ([99mTc]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. [99mTc]17 may be a potential probe for imaging β-amyloid plaques in Alzheimer’s brains.Keywords (keywords): 99mTc; Alzheimer’s disease; single photon emission computed tomography (SPECT) imaging; β-amyloid plaque
Co-reporter:Masahiro Ono, Yasufumi Fuchi, Takeshi Fuchigami, Nobuya Kobashi, Hiroyuki Kimura, Mamoru Haratake, Hideo Saji, and Morio Nakayama
ACS Medicinal Chemistry Letters 2010 Volume 1(Issue 8) pp:443
Publication Date(Web):August 2, 2010
DOI:10.1021/ml100140d
Two novel benzofuran derivatives coupled with 99mTc 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, 99mTc-BAT-BF showed higher affinity than 99mTc-MAMA-BF. In sections of brain tissue from an animal model of AD, 99mTc-BAT-BF clearly labeled β-amyloid plaques. In biodistribution experiments using normal mice, 99mTc-BAT-BF displayed high uptake soon after its injection and washed out from the brain rapidly, a highly desirable feature for an imaging agent. 99mTc-BAT-BF may be a potential probe for imaging β-amyloid plaques in Alzheimer's brains.Keywords (keywords): Alzheimer's disease; imaging; single photon emission computed tomography (SPECT); Tc-99m; β-amyloid plaque
Co-reporter:Yan Cheng, Masahiro Ono, Hiroyuki Kimura, Shinya Kagawa, Ryuichi Nishii, Hidekazu Kawashima, and Hideo Saji
ACS Medicinal Chemistry Letters 2010 Volume 1(Issue 7) pp:321
Publication Date(Web):July 11, 2010
DOI:10.1021/ml100082x
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 Ki values in the nanomolar range. Radiofluorinated 17, [18F]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 [18F]17 in Tg2576 mice. In conclusion, [18F]17 may be useful for detecting β-amyloid plaques in patients with AD.Keywords (keywords): Alzheimer's disease; benzofuran; fluorine-18; positron emission tomography (PET)
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Mamoru Haratake, Nobuya Kobashi, Hideo Saji, Morio Nakayama
Bioorganic & Medicinal Chemistry 2010 Volume 18(Issue 13) pp:4740-4746
Publication Date(Web):1 July 2010
DOI:10.1016/j.bmc.2010.05.013
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-1H-indole (2-PI) derivatives showed high affinity for Aβ42 aggregates with Ki 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.
Co-reporter:Yan Cheng, Masahiro Ono, Hiroyuki Kimura, Shinya Kagawa, Ryuichi Nishii, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2010 Volume 20(Issue 20) pp:6141-6144
Publication Date(Web):15 October 2010
DOI:10.1016/j.bmcl.2010.08.016
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 (Ki = 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.This Letter describes a novel 18F-labeled pyridyl benzofuran derivative ([18F]FPYBF-1) as a potential PET imaging probe for β-amyloid plaques in Alzheimer’s brains.
Co-reporter:Masahiro Ono, Ryoichi Ikeoka, Hiroyuki Watanabe, Hiroyuki Kimura, Takeshi Fuchigami, Mamoru Haratake, Hideo Saji, Morio Nakayama
Bioorganic & Medicinal Chemistry Letters 2010 Volume 20(Issue 19) pp:5743-5748
Publication Date(Web):1 October 2010
DOI:10.1016/j.bmcl.2010.08.004
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.Two Re/99mTc complexes based on flavone and aurone were tested as potential probes for imaging of cerebral β-amyloid plaques.
Co-reporter:Masahiro Ono, Manami Ishikawa, Hiroyuki Kimura, Shun Hayashi, Kenji Matsumura, Hiroyuki Watanabe, Yoichi Shimizu, Yan Cheng, Mengchao Cui, Hidekazu Kawashima, Hideo Saji
Bioorganic & Medicinal Chemistry Letters 2010 Volume 20(Issue 13) pp:3885-3888
Publication Date(Web):1 July 2010
DOI:10.1016/j.bmcl.2010.05.027
The imaging of β-amyloid (Aβ) aggregates in the brain may lead to the early detection of Alzheimer’s disease (AD) and monitoring of the progression and effectiveness of treatment. The purpose of this study was to develop dual modality SPECT and fluorescent probes based on boron dipyrromethane (BODIPY) as a core structure. We designed and synthesized an 125I-labeled derivative of BODIPY (BODIPY7). BODIPY7 had a Ki value of 108 nM for Aβ(1–42) aggregates and exhibited peaks of absorption/emission at 606/613 nm. It detected Aβ plaques in sections of brain tissue from an animal model of AD and displayed low uptake in the brain and high uptake in the liver in normal mice. Although additional modifications of the BODIPY scaffold are necessary to improve brain uptake, these results should aid the development of dual functional SPECT/fluorescent probes for the imaging of Aβ plaques in the brain.
Co-reporter:Masahiro Ono ; Rumi Watanabe ; Hidekazu Kawashima ; Yan Cheng ; Hiroyuki Kimura ; Hiroyuki Watanabe ; Mamoru Haratake ; Hideo Saji ;Morio Nakayama
Journal of Medicinal Chemistry 2009 Volume 52(Issue 20) pp:6394-6401
Publication Date(Web):September 16, 2009
DOI:10.1021/jm901057p
This paper describes the synthesis and biological evaluation of fluoro-pegylated (FPEG) chalcones for the imaging of β-amyloid (Aβ) 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 Aβ(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 Aβ 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 Aβ plaques was carried out using brain sections of AD model mice and an AD patient, the FPEG chalcone derivative 7c intensely labeled Aβ plaques. Taken together, the results suggest 7c to be a useful candidate PET tracer for detecting Aβ plaques in the brain of patients with AD.
Co-reporter:Yoshifumi Maya, Masahiro Ono, Hiroyuki Watanabe, Mamoru Haratake, Hideo Saji and Morio Nakayama
Bioconjugate Chemistry 2009 Volume 20(Issue 1) pp:95
Publication Date(Web):December 11, 2008
DOI:10.1021/bc8003292
We report a novel series of radioiodinated aurone derivatives as probes for imaging Aβ 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 Aβ aggregates (Ki = 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 Aβ plaques in the brain of AD.
Co-reporter:Masahiro Ono, Shun Hayashi, Hiroyuki Kimura, Hidekazu Kawashima, Morio Nakayama, Hideo Saji
Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 19) pp:7002-7007
Publication Date(Web):1 October 2009
DOI:10.1016/j.bmc.2009.08.032
We synthesized push–pull benzothiazole derivatives and evaluated their potential as β-amyloid imaging probes. In binding experiments in vitro, the benzothiazoles showed excellent affinity for synthetic Aβ(1-42) aggregates. β-Amyloid plaques in the mouse and human brain were clearly visualized with the benzothiazoles, reflecting the results in vitro. These compounds may be a useful scaffold for the development of novel PET/SPECT and fluorescent tracers for detecting β-amyloid in Alzheimer’s brains.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono, Ryoichi Ikeoka, Mamoru Haratake, Hideo Saji, Morio Nakayama
Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 17) pp:6402-6406
Publication Date(Web):1 September 2009
DOI:10.1016/j.bmc.2009.07.020
This paper describes the synthesis and biological evaluation of a new series of 2,5-diphenyl-1,3,4-oxadiazole (1,3,4-DPOD) derivatives for detecting β-amyloid plaques in Alzheimer’s brains. The affinity for β-amyloid plaques was assessed by an in vitro binding assay using pre-formed synthetic Aβ42 aggregates. The new series of 1,3,4-DPOD derivatives showed affinity for Aβ42 aggregates with Ki values ranging from 20 to 349 nM. The 1,3,4-DPOD derivatives clearly stained β-amyloid plaques in an animal model of Alzheimer’s disease, reflecting the affinity for Aβ42 aggregates in vitro. Compared to 3,5-diphenyl-1,2,4-oxadiazole (1,2,4-DPOD) derivatives, they displayed good penetration of and fast washout from the brain in biodistribution experiments using normal mice. The novel radioiodinated 1,3,4-DPOD derivatives may be useful probes for detecting β-amyloid plaques in the Alzheimer’s brain.
Co-reporter:Masahiro Ono, Rumi Watanabe, Hidekazu Kawashima, Tomoki Kawai, Hiroyuki Watanabe, Mamoru Haratake, Hideo Saji, Morio Nakayama
Bioorganic & Medicinal Chemistry 2009 17(5) pp: 2069-2076
Publication Date(Web):
DOI:10.1016/j.bmc.2009.01.025
Co-reporter:Masahiro Ono, Mamoru Haratake, Hideo Saji, Morio Nakayama
Bioorganic & Medicinal Chemistry 2008 Volume 16(Issue 14) pp:6867-6872
Publication Date(Web):15 July 2008
DOI:10.1016/j.bmc.2008.05.054
In the search for novel probes for the imaging in vivo of β-amyloid plaques in Alzheimer’s disease (AD) brain, we have synthesized and evaluated a series of 3,5-diphenyl-1,2,4-oxadiazole (DPOD) derivatives. The affinity for β-amyloid plaques was assessed by an in vitro-binding assay using pre-formed synthetic Aβ42 aggregates. The new series of DPOD derivatives showed excellent affinity for Aβ aggregates with Ki values ranging from 4 to 47 nM. In biodistribution experiments using normal mice, [125I]12, [125I]13, [125I]14, and [125I]15 examined displayed sufficient uptake for imaging, ranging from 2.2 to 3.3% ID/g. But the washout of the four ligands from the brain was relatively slow. Although additional modifications are necessary to improve the uptake and rapid clearance of non-specifically bound radiotracers, the DPOD pharmacophore with high-binding affinity for Aβ aggregates may be useful as a backbone structure to develop novel β-amyloid imaging agents.
Co-reporter:Hiroyuki Watanabe, Masahiro Ono and Hideo Saji
Chemical Communications 2015 - vol. 51(Issue 96) pp:NaN17127-17127
Publication Date(Web):2015/10/12
DOI:10.1039/C5CC06628J
In vivo fluorescence imaging of β-amyloid (Aβ) plaques in the brain is expected to be used as a new method for detecting Alzheimer's disease (AD). We synthesized novel push–pull dimethylaminothiophenyl (DTM) derivatives and evaluated their utility as in vivo fluorescence imaging probes targeting Aβ plaques. As a result, we found that DTM-2 is a promising fluorescent probe for Aβ plaques in the AD brains.
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