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Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [<jats:sup>18<\/jats:sup>F] fluspidine and [<jats:sup>18<\/jats:sup>F] fallypride PET, the purpose of this study was to assess in vivo target engagement\/receptor occupancy of pridopidine to the S1R and dopamine D2\/D3 receptor (D2\/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Using [<jats:sup>18<\/jats:sup>F] fluspidine PET (300\u00a0MBq, 0\u201390\u00a0min), 11 male HVs (pridopidine 0.5 to 90\u00a0mg; six dose groups) and three male patients with HD (pridopidine 90\u00a0mg) were investigated twice, without and 2\u00a0h after single dose of pridopidine. Using [<jats:sup>18<\/jats:sup>F] fallypride PET (200\u00a0MBq, 0\u2013210\u00a0min), four male HVs were studied without and 2\u00a0h following pridopidine administration (90\u00a0mg). Receptor occupancy was analyzed by the Lassen plot.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90\u00a0mg. S1R occupancy was 43% at 1\u00a0mg pridopidine. In contrast, at 90\u00a0mg pridopidine, the D2\/D3R occupancy was only minimal (~\u20093%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our PET findings indicate that at clinically relevant single dose of 90\u00a0mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2\/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine\u2019s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders.<\/jats:p>\n                <jats:p>Clinical <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/trials.gov\">Trials.gov<\/jats:ext-link> Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-020-05030-3","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T22:02:37Z","timestamp":1601416957000},"page":"1103-1115","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Sigma-1 and dopamine D2\/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study"],"prefix":"10.1007","volume":"48","author":[{"given":"Igor D.","family":"Grachev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp M.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg A.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Bronzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug","family":"Marsteller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Pastino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"Voges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rabinovich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Knebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Zientek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rullmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Sattler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Patt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilo","family":"Gerhards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kluge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Brust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha-Matti","family":"Savola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark F.","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Geva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swen","family":"Hesse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henryk","family":"Barthel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"Sabri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,29]]},"reference":[{"key":"5030_CR1","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/nrd.2018.133","volume":"17","author":"NS Caron","year":"2018","unstructured":"Caron NS, Dorsey ER, Hayden MR. 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Nature. 2016;532:527\u201330.","journal-title":"Nature."}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-020-05030-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-020-05030-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-020-05030-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T23:46:56Z","timestamp":1632872816000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-020-05030-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,29]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["5030"],"URL":"https:\/\/doi.org\/10.1007\/s00259-020-05030-3","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,29]]},"assertion":[{"value":"3 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Dr. Grachev was an employee of Teva Pharmaceuticals at the time of the study and is currently an employee of Guide Pharmaceutical Consulting. Drs. Gordon, Rabinovich, and Knebel are working for Teva Pharmaceuticals. Drs. Savola, Marsteller, and Pastino were employed by Teva Pharmaceuticals at the time of the study. Drs. Kluge, Bronzel, and Voges are staff members of ABX-CRO Advanced Pharmaceutical Services. Drs. Geva and Hayden who are now employed by Prilenia Therapeutics Development were former staff members of Teva Pharmaceuticals at the time of the study. In September 2018, Teva Pharmaceutical sold and transferred its rights pertaining to pridopidine to Prilenia Therapeutics. The remaining authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This study was approved by the local ethics committee, the Federal Institute for Drugs and Medical Devices and the German Federal Office for Radiation Protection, and was performed according to the World Medical Association Declaration of Helsinki 1964 and its later amendments or comparable ethical standards (Clinical  Identifier: NCT03019289; EUDRA-CT-Nr. 2016-001757-41). The PET study performed at the Department of Nuclear Medicine, University Hospital of Leipzig, Germany.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All study participants gave written informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}