title: Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses.
abstract: BACKGROUND
  Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D2 receptor (D2R) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding.
  
  
  OBJECTIVE
  The present study examined sigma-1R and D2R occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats.
  
  
  METHODS
  Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer (11)C-SA4503 (sigma-1R) or (11)C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with (11)C-raclopride. Cerebral (11)C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V T) calculated by Logan graphical analysis. (11)C-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model.
  
  
  RESULTS
  Cunningham-Lassen plots indicated sigma-1R occupancies of 57 ± 2 and 85 ± 2% after pretreatment of animals with 3 and 15 mg/kg pridopidine. A significant (44-66%) reduction of (11)C-raclopride binding was only observed at 60 mg/kg pridopidine.
  
  
  CONCLUSIONS
  At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of D2Rs. Significant D2R occupancy was only observed at a dose 20-fold higher than was required for sigma-1R occupancy. The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Sahlholm
authors.forename: Jurgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.forename: Bram
authors.initials: B
authors.lastname: Maas
authors.forename: Chantal
authors.initials: C
authors.lastname: Kwizera
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Nisha K
authors.initials: NK
authors.lastname: Ramakrishnan
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D008297:Male; D017072:Neostriatum / Q000378:metabolism*; D010879:Piperazines; D010880:Piperidines / Q000378:metabolism*; D020891:Raclopride; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D010879:Piperazines; D010880:Piperidines; D020891:Raclopride; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C101789:SA 4503; C483720:pridopidine