2-(2-[2-Dimethylaminothiazol-5-yl]Ethenyl)-6- (2-[Fluoro]Ethoxy)Benzoxazole: A Novel PET Agent for In Vivo Detection of Dense Amyloid Plaques in Alzheimer's Disease Patients
Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminot...
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| Veröffentlicht in: | The Journal of nuclear medicine (1978) 2007-04, Vol.48 (4), p.553-561 |
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| creator | Kudo, Yukitsuka Okamura, Nobuyuki Furumoto, Shozo Tashiro, Manabu Furukawa, Katsutoshi Maruyama, Masahiro Itoh, Masatoshi Iwata, Ren Yanai, Kazuhiko Arai, Hiroyuki |
| description | Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET.
The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis.
BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils.
These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients. |
| doi_str_mv | 10.2967/jnumed.106.037556 |
| format | Article |
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The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis.
BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils.
These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.</description><identifier>ISSN: 0161-5505</identifier><identifier>EISSN: 1535-5667</identifier><identifier>DOI: 10.2967/jnumed.106.037556</identifier><identifier>PMID: 17401091</identifier><identifier>CODEN: JNMEAQ</identifier><language>eng</language><publisher>United States: Soc Nuclear Med</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease - diagnosis ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid - chemistry ; Animals ; Benzoxazoles - pharmacokinetics ; Brain ; Clinical trials ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Permeability ; Positron-Emission Tomography - instrumentation ; Positron-Emission Tomography - methods ; R&D ; Radiopharmaceuticals - pharmacokinetics ; Research & development ; Studies ; Technological change ; Thiazoles - pharmacokinetics ; Tissues</subject><ispartof>The Journal of nuclear medicine (1978), 2007-04, Vol.48 (4), p.553-561</ispartof><rights>Copyright Society of Nuclear Medicine Apr 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-8f423ef12d393366c55c62a98e91f6732f5e8e64eb974b3e839b0fe8db61d2c63</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17401091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kudo, Yukitsuka</creatorcontrib><creatorcontrib>Okamura, Nobuyuki</creatorcontrib><creatorcontrib>Furumoto, Shozo</creatorcontrib><creatorcontrib>Tashiro, Manabu</creatorcontrib><creatorcontrib>Furukawa, Katsutoshi</creatorcontrib><creatorcontrib>Maruyama, Masahiro</creatorcontrib><creatorcontrib>Itoh, Masatoshi</creatorcontrib><creatorcontrib>Iwata, Ren</creatorcontrib><creatorcontrib>Yanai, Kazuhiko</creatorcontrib><creatorcontrib>Arai, Hiroyuki</creatorcontrib><title>2-(2-[2-Dimethylaminothiazol-5-yl]Ethenyl)-6- (2-[Fluoro]Ethoxy)Benzoxazole: A Novel PET Agent for In Vivo Detection of Dense Amyloid Plaques in Alzheimer's Disease Patients</title><title>The Journal of nuclear medicine (1978)</title><addtitle>J Nucl Med</addtitle><description>Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET.
The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis.
BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils.
These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alzheimer Disease - diagnosis</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid - chemistry</subject><subject>Animals</subject><subject>Benzoxazoles - pharmacokinetics</subject><subject>Brain</subject><subject>Clinical trials</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Middle Aged</subject><subject>Permeability</subject><subject>Positron-Emission Tomography - instrumentation</subject><subject>Positron-Emission Tomography - methods</subject><subject>R&D</subject><subject>Radiopharmaceuticals - pharmacokinetics</subject><subject>Research & development</subject><subject>Studies</subject><subject>Technological change</subject><subject>Thiazoles - 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diagnosis</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid - chemistry</topic><topic>Animals</topic><topic>Benzoxazoles - pharmacokinetics</topic><topic>Brain</topic><topic>Clinical trials</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Middle Aged</topic><topic>Permeability</topic><topic>Positron-Emission Tomography - instrumentation</topic><topic>Positron-Emission Tomography - methods</topic><topic>R&D</topic><topic>Radiopharmaceuticals - pharmacokinetics</topic><topic>Research & development</topic><topic>Studies</topic><topic>Technological change</topic><topic>Thiazoles - pharmacokinetics</topic><topic>Tissues</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kudo, Yukitsuka</creatorcontrib><creatorcontrib>Okamura, Nobuyuki</creatorcontrib><creatorcontrib>Furumoto, Shozo</creatorcontrib><creatorcontrib>Tashiro, Manabu</creatorcontrib><creatorcontrib>Furukawa, Katsutoshi</creatorcontrib><creatorcontrib>Maruyama, Masahiro</creatorcontrib><creatorcontrib>Itoh, Masatoshi</creatorcontrib><creatorcontrib>Iwata, Ren</creatorcontrib><creatorcontrib>Yanai, Kazuhiko</creatorcontrib><creatorcontrib>Arai, Hiroyuki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of nuclear medicine (1978)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kudo, Yukitsuka</au><au>Okamura, Nobuyuki</au><au>Furumoto, Shozo</au><au>Tashiro, Manabu</au><au>Furukawa, Katsutoshi</au><au>Maruyama, Masahiro</au><au>Itoh, Masatoshi</au><au>Iwata, Ren</au><au>Yanai, Kazuhiko</au><au>Arai, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2-(2-[2-Dimethylaminothiazol-5-yl]Ethenyl)-6- (2-[Fluoro]Ethoxy)Benzoxazole: A Novel PET Agent for In Vivo Detection of Dense Amyloid Plaques in Alzheimer's Disease Patients</atitle><jtitle>The Journal of nuclear medicine (1978)</jtitle><addtitle>J Nucl Med</addtitle><date>2007-04-01</date><risdate>2007</risdate><volume>48</volume><issue>4</issue><spage>553</spage><epage>561</epage><pages>553-561</pages><issn>0161-5505</issn><eissn>1535-5667</eissn><coden>JNMEAQ</coden><abstract>Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET.
The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis.
BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils.
These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.</abstract><cop>United States</cop><pub>Soc Nuclear Med</pub><pmid>17401091</pmid><doi>10.2967/jnumed.106.037556</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Adult Aged Aged, 80 and over Alzheimer Disease - diagnosis Alzheimer Disease - pathology Alzheimer's disease Amyloid - chemistry Animals Benzoxazoles - pharmacokinetics Brain Clinical trials Female Humans Male Mice Mice, Transgenic Middle Aged Permeability Positron-Emission Tomography - instrumentation Positron-Emission Tomography - methods R&D Radiopharmaceuticals - pharmacokinetics Research & development Studies Technological change Thiazoles - pharmacokinetics Tissues |
| title | 2-(2-[2-Dimethylaminothiazol-5-yl]Ethenyl)-6- (2-[Fluoro]Ethoxy)Benzoxazole: A Novel PET Agent for In Vivo Detection of Dense Amyloid Plaques in Alzheimer's Disease Patients |
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