{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T12:27:41Z","timestamp":1764937661146,"version":"3.41.2"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recently, the azepino[4,3\u2010<jats:italic>b<\/jats:italic>]indole\u20101\u2010one derivative <jats:bold>1<\/jats:bold> showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against <jats:italic>N<\/jats:italic>\u2010methyl\u2010\n<jats:sc>d<\/jats:sc>\u2010aspartate\u2010induced neuronal toxicity. Three 9\u2010R\u2010substituted (R\u2009=\u2009F, Br, OMe) congeners were investigated. The 9\u2010F derivative (<jats:bold>2a<\/jats:bold>) was found more potent as\u00a0BChE inhibitors\u00a0(half\u2010maximal inhibitory concentration value\u2009=\u200921\u2009nM) than <jats:bold>2b<\/jats:bold> (9\u2010Br) and <jats:bold>2c<\/jats:bold> (9\u2010OMe), achieving a residence time (38\u2009s), assessed by surface plasmon resonance,\u00a0threefold higher than that of <jats:bold>1<\/jats:bold>. To progress in featuring the in vivo pharmacological characterization of <jats:bold>2a<\/jats:bold>, herein the <jats:sup>18<\/jats:sup>F\u2010labeled congener <jats:bold>2a<\/jats:bold> was synthesized, by applying the aromatic <jats:sup>18<\/jats:sup>F\u2010fluorination method, and its whole\u2010body distribution in healthy mice, including brain penetration, was evaluated through positron\u00a0emission tomography\u00a0imaging. [<jats:sup>18<\/jats:sup>F]<jats:bold>2a<\/jats:bold> exhibited a rapid and high brain uptake (3.35\u2009\u00b1\u20090.26% ID\u2009g<jats:sup>\u22121<\/jats:sup> at 0.95\u2009\u00b1\u20090.15\u2009min after injection), followed by a rapid clearance (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>\u2009=\u20096.50\u2009\u00b1\u20090.93\u2009min), showing good blood\u2013brain barrier\u00a0crossing. After a transient liver accumulation of [<jats:sup>18<\/jats:sup>F]<jats:bold>2a<\/jats:bold>, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled <jats:bold>2a<\/jats:bold> affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild\u2010to\u2010moderate AD\u2010related dementias.<\/jats:p>","DOI":"10.1002\/ardp.202300491","type":"journal-article","created":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T02:55:19Z","timestamp":1703904919000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Radiosynthesis and whole\u2010body distribution in mice of a <sup>18<\/sup>F\u2010labeled azepino[4,3\u2010<i>b<\/i>]indole\u20101\u2010one derivative with multimodal activity for the treatment of Alzheimer's disease"],"prefix":"10.1002","volume":"357","author":[{"given":"Sang Hee","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Purgatorio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Samarelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Catto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nunzio","family":"Denora","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Grazia","family":"Morgese","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine University of Foggia  Foggia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Tucci","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine University of Foggia  Foggia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigia","family":"Trabace","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine University of Foggia  Foggia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Republic of Korea"},{"name":"Center for Nanomolecular Imaging and Innovative Drug Development Advanced Institutes of Convergence Technology  Suwon Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung Chul","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Republic of Korea"},{"name":"Center for Nanomolecular Imaging and Innovative Drug Development Advanced Institutes of Convergence Technology  Suwon Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-1981","authenticated-orcid":false,"given":"Modesto","family":"de Candia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cosimo D.","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2010Pharmaceutical Sciences University of Bari Aldo Moro  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"https:\/\/www.alzint.org\/resource\/world-alzheimer-report-2022\/in the Alzheimer's Disease International Organiozation website."},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2015.990884"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-045115"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-802851-3.00001-2"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160763"},{"volume-title":"The Biology of Cholinesterases","year":"1974","author":"Silver A.","key":"e_1_2_7_7_1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389203720666191107094949"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(97)00016-7"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(76)91936-X"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(77)90073-9"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508575102"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31823cc7a6"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011832"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2012.08.009"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2006.06.055"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.09.037"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.05.062"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000583"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(61)90145-9"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2017.08.031"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.05.004"},{"key":"e_1_2_7_23_1","first-page":"236","volume":"6","author":"Sheline Y. I.","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107411108"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2002.tb00215.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2004.02.002"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11050686"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025084415833"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2006.06.003"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.8b03167"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn769"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19980413)393:3<374::AID-CNE8>3.0.CO;2-Z"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11307-021-01584-2"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.54589"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-021-05617-4"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27185931"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci300367a"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mibio.2003.09.014"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.112.104810"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000942"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.7b00351"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm5010754"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26175208"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27134269"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990500"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2017.12.046"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.202300491","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T03:59:50Z","timestamp":1710820790000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.202300491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,29]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/ardp.202300491"],"URL":"https:\/\/doi.org\/10.1002\/ardp.202300491","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"type":"print","value":"0365-6233"},{"type":"electronic","value":"1521-4184"}],"subject":[],"published":{"date-parts":[[2023,12,29]]},"assertion":[{"value":"2023-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2300491"}}