{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T23:38:43Z","timestamp":1778888323257,"version":"3.51.4"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T00:00:00Z","timestamp":1545350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pridopidine, in development for Huntington's disease, may modulate aberrant <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced effects including <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia (LID).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The pharmacokinetic profile and effects of pridopidine (15\u201030\u2009mg\/kg) on parkinsonism, dyskinesia, and quality of on\u2010time, in combination with <jats:sc>l<\/jats:sc>\u2010dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to \u03c3<jats:sub>1<\/jats:sub> and dopamine D<jats:sub>2<\/jats:sub> receptors, in vivo PET imaging, and pharmacokinetic profiling across different species.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pridopidine produced a dose\u2010dependent reduction in dyskinesia (up to 71%, 30\u2009mg\/kg) and decreased the duration of on\u2010time with disabling dyskinesia evoked by <jats:sc>l<\/jats:sc>\u2010dopa by 37% (20\u2009mg\/kg) and 60% (30\u2009mg\/kg). Pridopidine did not compromise the anti\u2010parkinsonian benefit of <jats:sc>l<\/jats:sc>\u2010dopa. Plasma exposures following the ineffective dose (15\u2009mg\/kg) were associated with full \u03c3<jats:sub>1<\/jats:sub> occupancy (&gt;80%), suggesting that \u03c3<jats:sub>1<\/jats:sub> engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20\u201030\u2009mg\/kg), while providing full \u03c3<jats:sub>1<\/jats:sub> occupancy, provide only modest dopamine D<jats:sub>2<\/jats:sub> occupancy (&lt;40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic\u2010\u03b1<jats:sub>2C<\/jats:sub>, dopamine\u2010D<jats:sub>3<\/jats:sub>, and serotoninergic\u20105\u2010HT<jats:sub>1A<\/jats:sub> sites) to a higher degree than D<jats:sub>2<\/jats:sub> and might contribute to the antidyskinetic actions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of <jats:sc>l<\/jats:sc>\u2010dopa. Although the actions of pridopidine were associated with full \u03c3<jats:sub>1<\/jats:sub> occupancy, effective exposures are more likely associated with occupancy of additional, non\u2010sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. \u00a9 2018 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27565","type":"journal-article","created":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T17:32:55Z","timestamp":1545413575000},"page":"708-716","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Pridopidine, a clinic\u2010ready compound, reduces 3,4\u2010dihydroxyphenylalanine\u2010induced dyskinesia in Parkinsonian macaques"],"prefix":"10.1002","volume":"34","author":[{"given":"Tom H.","family":"Johnston","sequence":"first","affiliation":[{"name":"Atuka Inc  Toronto Ontario Canada"},{"name":"Krembil Research Institute Toronto Western Hospital, University Health Network  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Geva","sequence":"additional","affiliation":[{"name":"Prilenia Therapeutics Development Ltd.  (formerly 4) Herzliya Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilach","family":"Steiner","sequence":"additional","affiliation":[{"name":"Global Research and Development Teva Pharmaceutical Industries, Ltd.  Netanya Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aric","family":"Orbach","sequence":"additional","affiliation":[{"name":"Global Research and Development Teva Pharmaceutical Industries, Ltd.  Netanya Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spyros","family":"Papapetropoulos","sequence":"additional","affiliation":[{"name":"Global Research and Development Teva Pharmaceutical Industries, Ltd.  Netanya Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha\u2010Matti","family":"Savola","sequence":"additional","affiliation":[{"name":"Teva Pharmaceuticals International, GmbH  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian J.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Rewind Therapeutics Leuven  (formerly 4) Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Ravenscroft","sequence":"additional","affiliation":[{"name":"Atuka Inc  Toronto Ontario Canada"},{"name":"Krembil Research Institute Toronto Western Hospital, University Health Network  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Hill","sequence":"additional","affiliation":[{"name":"Atuka Inc  Toronto Ontario Canada"},{"name":"Krembil Research Institute Toronto Western Hospital, University Health Network  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan H.","family":"Fox","sequence":"additional","affiliation":[{"name":"Movement Disorders Clinic, Toronto Western Hospital University Health Network  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M.","family":"Brotchie","sequence":"additional","affiliation":[{"name":"Atuka Inc  Toronto Ontario Canada"},{"name":"Krembil Research Institute Toronto Western Hospital, University Health Network  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph","family":"Laufer","sequence":"additional","affiliation":[{"name":"Lysogene S.A.  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