Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [
Dopamine D2/D3 receptor occupancy
Huntington disease
PET
Pridopidine
Sigma-1 receptor occupancy
[18F]fluspidine
Journal
European journal of nuclear medicine and molecular imaging
ISSN: 1619-7089
Titre abrégé: Eur J Nucl Med Mol Imaging
Pays: Germany
ID NLM: 101140988
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
03
06
2020
accepted:
07
09
2020
pubmed:
1
10
2020
medline:
29
5
2021
entrez:
30
9
2020
Statut:
ppublish
Résumé
Pridopidine is an investigational drug for Huntington disease (HD). 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 [ Using [ 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 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Our PET findings indicate that at clinically relevant single dose of 90 mg, 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's 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. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
Identifiants
pubmed: 32995944
doi: 10.1007/s00259-020-05030-3
pii: 10.1007/s00259-020-05030-3
pmc: PMC8041674
doi:
Substances chimiques
1'-benzyl-3-(2-fluoroethyl)-3H-spiro((2)benzofuran-1,4'-piperidine)
0
Benzamides
0
Benzofurans
0
Piperidines
0
Receptors, Dopamine D2
0
Receptors, Dopamine D3
0
fallypride
G9FWZ369GX
pridopidine
HD4TW8S2VK
Dopamine
VTD58H1Z2X
Banques de données
ClinicalTrials.gov
['NCT03019289']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1103-1115Références
Caron NS, Dorsey ER, Hayden MR. Therapeutic approaches to Huntington disease: from the bench to the clinic. Nat Rev Drug Discov. 2018;17:729–50.
doi: 10.1038/nrd.2018.133
Mancuso R, Navarro X. Amyotrophic lateral sclerosis: current perspectives from basic research to the clinic. Prog Neurobiol. 2015;133:1–26.
doi: 10.1016/j.pneurobio.2015.07.004
Dyhring T, Nielsen EØ, Sonesson C, Pettersson F, Karlsson J, Svensson P, et al. The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties. Eur J Pharmacol. 2010;628:19–26.
doi: 10.1016/j.ejphar.2009.11.025
Waters S, Tedroff J, Ponten H, Klamer D, Sonesson C, Waters N. Pridopidine: overview of pharmacology and rationale for its use in Huntington's disease. J Huntingtons Dis. 2018;7:1–16.
doi: 10.3233/JHD-170267
Rung JP, Rung E, Helgeson L, Johansson AM, Svensson K, Carlsson A, et al. Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J Neural Transm (Vienna). 2018;115:899–908.
doi: 10.1007/s00702-008-0038-3
Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, et al. Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques. Mov Disord. 2019;34:708–16.
doi: 10.1002/mds.27565
Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and (−)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013;18:12–4.
doi: 10.1038/mp.2012.3
Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, et al. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacology. 2015;232:3443–53.
doi: 10.1007/s00213-015-3997-8
Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci. 2010;31:557–66.
doi: 10.1016/j.tips.2010.08.007
Ruscher K, Wieloch T. The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. J Pharmacol Sci. 2015;127:30–5.
doi: 10.1016/j.jphs.2014.11.011
Al-Saif A, Al-Mohanna F, Bohlega SA. Mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011;70:913–9.
doi: 10.1002/ana.22534
Gregianin E, Pallafacchina G, Zanin S, Crippa V, Rusmini P, Poletti A, et al. Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling. Hum Mol Genet. 2016;25:3741–53.
doi: 10.1093/hmg/ddw220
Squitieri F, Di Pardo A, Favellato M, Amico E, Maglione V, Frati L. Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. J Cell Mol Med. 2015;19:2540–8.
doi: 10.1111/jcmm.12604
Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. Pridopidine activates neuroprotective pathways impaired in Huntington disease. Hum Mol Genet. 2016;25:3975–87.
doi: 10.1093/hmg/ddw238
Francardo V, Geva M, Bez F, Denis Q, Steiner L, Hayden MR, et al. Pridopidine induces functional neurorestoration via the sigma-1 receptor in a mouse model of Parkinson's disease. Neurotherapeutics. 2019;16:465–79.
doi: 10.1007/s13311-018-00699-9
Ionescu A, Gradus T, Altman T, Maimon R, Saraf Avraham N, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1G93A model. Cell Death Dis. 2019;10:210. https://doi.org/10.1038/s41419-019-1451-2 .
doi: 10.1038/s41419-019-1451-2
pubmed: 30824685
pmcid: 6397200
Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis. 2017;97:46–59.
doi: 10.1016/j.nbd.2016.10.006
Reilmann R, McGarry A, Grachev ID, Savola JM, Borowsky B, Eyal E, et al. European Huntington's disease network; Huntington study group investigators. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019;18:165–76.
doi: 10.1016/S1474-4422(18)30391-0
Fischer S, Wiese C, Maestrup EG, Hiller A, Deuther-Conrad W, Scheunemann M, et al. Molecular imaging of σ receptors: synthesis and evaluation of the potent σ1 selective radioligand [
doi: 10.1007/s00259-010-1658-z
Brust P, Deuther-Conrad W, Becker G, Patt M, Donat CK, Stittsworth S, et al. Distinctive in vivo kinetics of the new sigma-1 receptor ligands (R)-(+)- and (S)-(-)-
doi: 10.2967/jnumed.114.137562
Baum E, Cai Z, Bois F, Holden D, Lin SF, Lara-Jaime T, et al. PET imaging evaluation of four σ1 radiotracers in nonhuman primates. J Nucl Med. 2017;58:982–8.
doi: 10.2967/jnumed.116.188052
Kranz M, Sattler B, Wüst N, Deuther-Conrad W, Patt M, Meyer PM, et al. Evaluation of the enantiomer specific biokinetics and radiation doses of [(
doi: 10.3390/molecules21091164
Becker GA, Meyer PM, Patt M, Hesse S, Luthardt J, Patt T, et al. Kinetic modeling of the new sigma-1 receptor ligand (-)-[
Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M, et al. Brain imaging of
doi: 10.1002/syn.10128
Gründer G, Fellows C, Janouschek H, Veselinovic T, Boy C, Bröcheler A, et al. Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [
doi: 10.1176/appi.ajp.2008.07101574
Huntington Study Group. Unified Huntington's disease rating scale: reliability and consistency. Mov Disord. 1996;11:136–42.
doi: 10.1002/mds.870110204
Shannon KM. Pridopidine for the treatment of Huntington's disease. Expert Opin Investig Drugs. 2016;25:485–92.
doi: 10.1517/13543784.2016.1153627
Maisonial-Besset A, Funke U, Wenzel B, Fischer S, Holl K, Wünsch B, et al. Automation of the radiosynthesis and purification procedures for [
doi: 10.1016/j.apradiso.2013.10.015
Piel M, Schmitt U, Bausbacher N, Buchholz HG, Gründer G, Hiemke C, et al. Evaluation of P-glycoprotein (abcb1a/b) modulation of [(
doi: 10.1016/j.neuropharm.2013.04.062
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, et al. Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp. 2000;10:120–31.
doi: 10.1002/1097-0193(200007)10:3<120::AID-HBM30>3.0.CO;2-8
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–89.
doi: 10.1006/nimg.2001.0978
Patt M, Becker GA, Grossmann U, Habermann B, Schildan A, Wilke S, et al. Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[(
doi: 10.1016/j.nucmedbio.2014.03.018
Stober T, Wussow W, Schimrigk K. Bicaudate diameter - the most specific and simple CT parameter in the diagnosis of Huntington's disease. Neuroradiology. 1984;26:25–8.
doi: 10.1007/BF00328198
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-
doi: 10.1038/jcbfm.1990.127
Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–8.
doi: 10.1006/nimg.1996.0066
Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50.
doi: 10.1038/jcbfm.2009.190
Kirby S, Brain P, Jones B. Fitting E (max) models to clinical trial dose-response data. Pharm Stat. 2011;10:143–9.
doi: 10.1002/pst.432
Helldén A, Panagiotidis G, Johansson P, Waters N, Waters S, Tedroff J, et al. The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans. Eur J Clin Pharmacol. 2012;68:1281–6.
doi: 10.1007/s00228-012-1248-z
Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiol Dis. 2019;129:118–29.
doi: 10.1016/j.nbd.2019.05.009
Garcia-Miralles M, Geva M, Tan JY, Yusof NABM, Cha Y, Kusko R, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017;2(23):pii: 95665. https://doi.org/10.1172/jci.insight.95665 .
doi: 10.1172/jci.insight.95665
Chu UB, Ruoho AE. Biochemical pharmacology of the sigma-1 receptor. Mol Pharmacol. 2016;89:142–53.
doi: 10.1124/mol.115.101170
Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human σ1 receptor. Nature. 2016;532:527–30.
doi: 10.1038/nature17391