New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects
σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synt...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-10, Vol.55 (19), p.8272-8282 |
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| container_title | Journal of medicinal chemistry |
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| creator | James, Michelle L Shen, Bin Zavaleta, Cristina L Nielsen, Carsten H Mesangeau, Christophe Vuppala, Pradeep K Chan, Carmel Avery, Bonnie A Fishback, James A Matsumoto, Rae R Gambhir, Sanjiv S McCurdy, Christopher R Chin, Frederick T |
| description | σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects. |
| doi_str_mv | 10.1021/jm300371c |
| format | Article |
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Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300371c</identifier><identifier>PMID: 22853801</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Azepines - chemical synthesis ; Azepines - chemistry ; Azepines - pharmacokinetics ; Benzothiazoles - chemical synthesis ; Benzothiazoles - chemistry ; Benzothiazoles - pharmacokinetics ; Bone and Bones - diagnostic imaging ; Bone and Bones - metabolism ; Brain - diagnostic imaging ; Brain - metabolism ; CHO Cells ; Cricetinae ; Cricetulus ; Fluorine Radioisotopes ; In Vitro Techniques ; Liver - diagnostic imaging ; Liver - metabolism ; Mice ; Mice, Inbred BALB C ; Positron-Emission Tomography ; Radiopharmaceuticals - chemical synthesis ; Radiopharmaceuticals - chemistry ; Radiopharmaceuticals - pharmacokinetics ; Rats ; Receptors, sigma - metabolism ; Sigma-1 Receptor ; Tissue Distribution</subject><ispartof>Journal of medicinal chemistry, 2012-10, Vol.55 (19), p.8272-8282</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a405t-b2ee3e936e5151af0d4043712752c295f23edc2c11bdc969254ecc634e19a2683</citedby><cites>FETCH-LOGICAL-a405t-b2ee3e936e5151af0d4043712752c295f23edc2c11bdc969254ecc634e19a2683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm300371c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300371c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22853801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>James, Michelle L</creatorcontrib><creatorcontrib>Shen, Bin</creatorcontrib><creatorcontrib>Zavaleta, Cristina L</creatorcontrib><creatorcontrib>Nielsen, Carsten H</creatorcontrib><creatorcontrib>Mesangeau, Christophe</creatorcontrib><creatorcontrib>Vuppala, Pradeep K</creatorcontrib><creatorcontrib>Chan, Carmel</creatorcontrib><creatorcontrib>Avery, Bonnie A</creatorcontrib><creatorcontrib>Fishback, James A</creatorcontrib><creatorcontrib>Matsumoto, Rae R</creatorcontrib><creatorcontrib>Gambhir, Sanjiv S</creatorcontrib><creatorcontrib>McCurdy, Christopher R</creatorcontrib><creatorcontrib>Chin, Frederick T</creatorcontrib><title>New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.</description><subject>Animals</subject><subject>Azepines - chemical synthesis</subject><subject>Azepines - chemistry</subject><subject>Azepines - pharmacokinetics</subject><subject>Benzothiazoles - chemical synthesis</subject><subject>Benzothiazoles - chemistry</subject><subject>Benzothiazoles - pharmacokinetics</subject><subject>Bone and Bones - diagnostic imaging</subject><subject>Bone and Bones - metabolism</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Fluorine Radioisotopes</subject><subject>In Vitro Techniques</subject><subject>Liver - diagnostic imaging</subject><subject>Liver - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Positron-Emission Tomography</subject><subject>Radiopharmaceuticals - chemical synthesis</subject><subject>Radiopharmaceuticals - chemistry</subject><subject>Radiopharmaceuticals - pharmacokinetics</subject><subject>Rats</subject><subject>Receptors, sigma - metabolism</subject><subject>Sigma-1 Receptor</subject><subject>Tissue Distribution</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkNFKwzAUhoMobk4vfAHJjeAuqslJ27U3goypg6FjzuuSpmmXsjYj6Sa7E3wCn8x38EnMmA4Fr86B_zv_4f8ROqXkkhKgV2XFCGE9KvZQmwZAPD8i_j5qEwLgQQishY6sLYmDKLBD1AKIAhYR2kbpg3zBY21VY3SNB5WyVrllqitdGL6YrfHFeDDt4gnPlJ6rgtcZzrXBw4oXqi7wx9vn6zvFEynkotHGYlXjkVptpKdlWkrR2GN0kPO5lSffs4OebwfT_r03erwb9m9GHvdJ0HgpSMlkzEIZ0IDynGQ-8V0o6AUgIA5yYDITIChNMxGHMQS-FCJkvqQxhzBiHXS99V0s08qhsm4MnycLoypu1onmKvmr1GqWFHqV-JSEseumg7pbA2G0tUbmu1tKkk3Rya5ox579frYjf5p1wPkW4MImpV6a2mX_x-gLImmGnQ</recordid><startdate>20121011</startdate><enddate>20121011</enddate><creator>James, Michelle L</creator><creator>Shen, Bin</creator><creator>Zavaleta, Cristina L</creator><creator>Nielsen, Carsten H</creator><creator>Mesangeau, Christophe</creator><creator>Vuppala, Pradeep K</creator><creator>Chan, Carmel</creator><creator>Avery, Bonnie A</creator><creator>Fishback, James A</creator><creator>Matsumoto, Rae R</creator><creator>Gambhir, Sanjiv S</creator><creator>McCurdy, Christopher R</creator><creator>Chin, Frederick T</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20121011</creationdate><title>New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects</title><author>James, Michelle L ; Shen, Bin ; Zavaleta, Cristina L ; Nielsen, Carsten H ; Mesangeau, Christophe ; Vuppala, Pradeep K ; Chan, Carmel ; Avery, Bonnie A ; Fishback, James A ; Matsumoto, Rae R ; Gambhir, Sanjiv S ; McCurdy, Christopher R ; Chin, Frederick T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-b2ee3e936e5151af0d4043712752c295f23edc2c11bdc969254ecc634e19a2683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Azepines - chemical synthesis</topic><topic>Azepines - chemistry</topic><topic>Azepines - pharmacokinetics</topic><topic>Benzothiazoles - chemical synthesis</topic><topic>Benzothiazoles - chemistry</topic><topic>Benzothiazoles - pharmacokinetics</topic><topic>Bone and Bones - diagnostic imaging</topic><topic>Bone and Bones - metabolism</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - metabolism</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Fluorine Radioisotopes</topic><topic>In Vitro Techniques</topic><topic>Liver - diagnostic imaging</topic><topic>Liver - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Positron-Emission Tomography</topic><topic>Radiopharmaceuticals - chemical synthesis</topic><topic>Radiopharmaceuticals - chemistry</topic><topic>Radiopharmaceuticals - pharmacokinetics</topic><topic>Rats</topic><topic>Receptors, sigma - metabolism</topic><topic>Sigma-1 Receptor</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>James, Michelle L</creatorcontrib><creatorcontrib>Shen, Bin</creatorcontrib><creatorcontrib>Zavaleta, Cristina L</creatorcontrib><creatorcontrib>Nielsen, Carsten H</creatorcontrib><creatorcontrib>Mesangeau, Christophe</creatorcontrib><creatorcontrib>Vuppala, Pradeep K</creatorcontrib><creatorcontrib>Chan, Carmel</creatorcontrib><creatorcontrib>Avery, Bonnie A</creatorcontrib><creatorcontrib>Fishback, James A</creatorcontrib><creatorcontrib>Matsumoto, Rae R</creatorcontrib><creatorcontrib>Gambhir, Sanjiv S</creatorcontrib><creatorcontrib>McCurdy, Christopher R</creatorcontrib><creatorcontrib>Chin, Frederick T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>James, Michelle L</au><au>Shen, Bin</au><au>Zavaleta, Cristina L</au><au>Nielsen, Carsten H</au><au>Mesangeau, Christophe</au><au>Vuppala, Pradeep K</au><au>Chan, Carmel</au><au>Avery, Bonnie A</au><au>Fishback, James A</au><au>Matsumoto, Rae R</au><au>Gambhir, Sanjiv S</au><au>McCurdy, Christopher R</au><au>Chin, Frederick T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-10-11</date><risdate>2012</risdate><volume>55</volume><issue>19</issue><spage>8272</spage><epage>8282</epage><pages>8272-8282</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22853801</pmid><doi>10.1021/jm300371c</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Azepines - chemical synthesis Azepines - chemistry Azepines - pharmacokinetics Benzothiazoles - chemical synthesis Benzothiazoles - chemistry Benzothiazoles - pharmacokinetics Bone and Bones - diagnostic imaging Bone and Bones - metabolism Brain - diagnostic imaging Brain - metabolism CHO Cells Cricetinae Cricetulus Fluorine Radioisotopes In Vitro Techniques Liver - diagnostic imaging Liver - metabolism Mice Mice, Inbred BALB C Positron-Emission Tomography Radiopharmaceuticals - chemical synthesis Radiopharmaceuticals - chemistry Radiopharmaceuticals - pharmacokinetics Rats Receptors, sigma - metabolism Sigma-1 Receptor Tissue Distribution |
| title | New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects |
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