Z-IQNP : a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease
The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydro...
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| creator | NOBUHARA, K HALLDIN, C SWAHN, C.-G LARSSON, S. A SCHNELL, P.-O SEDVALL, G HALL, H KARLSSON, P FARDE, L HILTUNEN, J MCPHERSON, D. W SAVONEN, A BERGSTROM, K. A PAULI, S |
| description | The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype.
The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo.
Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey.
Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo.
This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum. |
| doi_str_mv | 10.1007/s002139900356 |
| format | Article |
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The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo.
Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey.
Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo.
This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.</description><identifier>ISSN: 0033-3158</identifier><identifier>EISSN: 1432-2072</identifier><identifier>DOI: 10.1007/s002139900356</identifier><identifier>PMID: 10789882</identifier><identifier>CODEN: PSYPAG</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>60 APPLIED LIFE SCIENCES ; ACETYLCHOLINE ; Acetylcholine receptors (muscarinic) ; Affinity ; Alzheimer Disease - diagnostic imaging ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Animals ; Autoradiography ; BASIC BIOLOGICAL SCIENCES ; Binding, Competitive ; Biological and medical sciences ; Brain ; Brain - diagnostic imaging ; Brain - metabolism ; Brain - pathology ; Cerebellum ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; DISEASES ; Humans ; Iodine Radioisotopes ; Macaca fascicularis ; Medical sciences ; Neurodegenerative diseases ; Neuroimaging ; Neurology ; Quinuclidines - chemistry ; Quinuclidines - metabolism ; Radioligand Assay ; Receptor density ; Receptors, Muscarinic - metabolism ; Scopolamine ; SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY ; Stereoisomerism ; Tomography, Emission-Computed, Single-Photon</subject><ispartof>PSYCHOPHARMACOLOGY, 2000-03, Vol.149 (1), p.45-55</ispartof><rights>2000 INIST-CNRS</rights><rights>Springer-Verlag Berlin Heidelberg 2000.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3569-908dc91d2ff507c650af904b4b1a324f05a43ae67e3d73749f5832edf579dca83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1315680$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10789882$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/815165$$D View this record in Osti.gov$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:16476708$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>NOBUHARA, K</creatorcontrib><creatorcontrib>HALLDIN, C</creatorcontrib><creatorcontrib>SWAHN, C.-G</creatorcontrib><creatorcontrib>LARSSON, S. A</creatorcontrib><creatorcontrib>SCHNELL, P.-O</creatorcontrib><creatorcontrib>SEDVALL, G</creatorcontrib><creatorcontrib>HALL, H</creatorcontrib><creatorcontrib>KARLSSON, P</creatorcontrib><creatorcontrib>FARDE, L</creatorcontrib><creatorcontrib>HILTUNEN, J</creatorcontrib><creatorcontrib>MCPHERSON, D. W</creatorcontrib><creatorcontrib>SAVONEN, A</creatorcontrib><creatorcontrib>BERGSTROM, K. A</creatorcontrib><creatorcontrib>PAULI, S</creatorcontrib><creatorcontrib>ORNL Oak Ridge National Laboratory</creatorcontrib><title>Z-IQNP : a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease</title><title>PSYCHOPHARMACOLOGY</title><addtitle>Psychopharmacology (Berl)</addtitle><description>The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype.
The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo.
Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey.
Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo.
This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>ACETYLCHOLINE</subject><subject>Acetylcholine receptors (muscarinic)</subject><subject>Affinity</subject><subject>Alzheimer Disease - diagnostic imaging</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Autoradiography</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Brain</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Cerebellum</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>DISEASES</subject><subject>Humans</subject><subject>Iodine Radioisotopes</subject><subject>Macaca fascicularis</subject><subject>Medical sciences</subject><subject>Neurodegenerative diseases</subject><subject>Neuroimaging</subject><subject>Neurology</subject><subject>Quinuclidines - chemistry</subject><subject>Quinuclidines - metabolism</subject><subject>Radioligand Assay</subject><subject>Receptor density</subject><subject>Receptors, Muscarinic - metabolism</subject><subject>Scopolamine</subject><subject>SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY</subject><subject>Stereoisomerism</subject><subject>Tomography, Emission-Computed, Single-Photon</subject><issn>0033-3158</issn><issn>1432-2072</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFks9vFCEUx4nR2LV69GowGj2N8mNmAG_NpmqTRmusFy-EhccudQZGmImpf700u7HqRS6Qbz55vO97X4QeU_KKEiJeF0IY5UoRwrv-DlrRlrOGEcHuolXVeMNpJ4_Qg1KuSD2tbO-jI0qEVFKyFUpfm7NPHy7wG2zwlGaIczADzsaFNIStiQ77lPHni9P1JQ6j2Ya4xcnjcSnW5BCDxcbCfD3YXeUj4AwWpjnlgkPEJ8PPHYQR8suCXShgCjxE97wZCjw63Mfoy9vTy_X75vzju7P1yXljqw3VKCKdVdQx7zsibN8R4xVpN-2GGs5aTzrTcgO9AO4EF63yneQMnO-EctZIfoyafd3yA6Zlo6dcu8_XOpmgD9K3-gLdE6qEqvzTPZ_KXHUbZrA7m2IEO2tJO9p3lXmxZ6acvi9QZj2GYmEYTIS0FC3qWFkv5X9BKqtHxm5-ffYPeJWWHOtgNKdUCNGrlt96sTmVksH_dkOJvgmB_isElX9yqLpsRnB_0PutV-D5ATB1jYPPJtpQbrkamV4S_gsI37d6</recordid><startdate>200003</startdate><enddate>200003</enddate><creator>NOBUHARA, K</creator><creator>HALLDIN, C</creator><creator>SWAHN, C.-G</creator><creator>LARSSON, S. 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A ; SCHNELL, P.-O ; SEDVALL, G ; HALL, H ; KARLSSON, P ; FARDE, L ; HILTUNEN, J ; MCPHERSON, D. W ; SAVONEN, A ; BERGSTROM, K. 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A</au><au>SCHNELL, P.-O</au><au>SEDVALL, G</au><au>HALL, H</au><au>KARLSSON, P</au><au>FARDE, L</au><au>HILTUNEN, J</au><au>MCPHERSON, D. W</au><au>SAVONEN, A</au><au>BERGSTROM, K. A</au><au>PAULI, S</au><aucorp>ORNL Oak Ridge National Laboratory</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Z-IQNP : a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease</atitle><jtitle>PSYCHOPHARMACOLOGY</jtitle><addtitle>Psychopharmacology (Berl)</addtitle><date>2000-03</date><risdate>2000</risdate><volume>149</volume><issue>1</issue><spage>45</spage><epage>55</epage><pages>45-55</pages><issn>0033-3158</issn><eissn>1432-2072</eissn><coden>PSYPAG</coden><abstract>The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype.
The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo.
Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey.
Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo.
This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>10789882</pmid><doi>10.1007/s002139900356</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | PSYCHOPHARMACOLOGY, 2000-03, Vol.149 (1), p.45-55 |
| issn | 0033-3158 1432-2072 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_601979 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 60 APPLIED LIFE SCIENCES ACETYLCHOLINE Acetylcholine receptors (muscarinic) Affinity Alzheimer Disease - diagnostic imaging Alzheimer Disease - metabolism Alzheimer's disease Animals Autoradiography BASIC BIOLOGICAL SCIENCES Binding, Competitive Biological and medical sciences Brain Brain - diagnostic imaging Brain - metabolism Brain - pathology Cerebellum Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DISEASES Humans Iodine Radioisotopes Macaca fascicularis Medical sciences Neurodegenerative diseases Neuroimaging Neurology Quinuclidines - chemistry Quinuclidines - metabolism Radioligand Assay Receptor density Receptors, Muscarinic - metabolism Scopolamine SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY Stereoisomerism Tomography, Emission-Computed, Single-Photon |
| title | Z-IQNP : a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease |
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