Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

Psychopharmacology, Jul 2015

Rationale 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. Objectives 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 11C-SA4503 (sigma-1R) or 11C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with 11C-raclopride. Cerebral 11C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V T) calculated by Logan graphical analysis. 11C-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 11C-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.

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Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses Kristoffer Sahlholm 0 1 2 Jurgen W. A. Sijbesma 0 1 2 Bram Maas 0 1 2 Chantal Kwizera 0 1 2 Daniel Marcellino 0 1 2 Nisha K. Ramakrishnan 0 1 2 Rudi A. J. O. Dierckx 0 1 2 Philip H. Elsinga 0 1 2 Aren van Waarde 0 1 2 0 Present address: Department of Neuroscience, Karolinska Institutet , 171 77 Stockholm , Sweden 1 Department of Physiology and Institute of Biomedical Technology (ITB), Center for Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna School of Medicine , Tenerife , Spain 2 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen , Groningen , The Netherlands Rationale 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. Objectives 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 11C-SA4503 (sigma-1R) or 11C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with 11Craclopride. Cerebral 11C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (VT) calculated by Logan graphical analysis. 11Craclopride binding was quantified using striatum-tocerebellum ratios and binding potentials calculated with a simplified reference tissue model. MicroPET; Kinetic analysis; 11C-SA4503; 11C-raclopride; Receptor occupancy - Aren van Waarde Pridopidine (also known as ACR16 or Huntexil) is a phenylpiperidine compound undergoing clinical trials for treatment of motor symptoms in Huntington’s disease (de Yebenes et al. 2011; Kieburtz et al. 2013; for the ongoing Pride-HD trial, see NCT02006472 at clinicaltrials.gov). Moreover, pridopidine has shown promising results in limited trials for schizophrenia and Parkinson’s disease (Ponten et al. 2010). The drug displays micromolar affinity for the dopamine D2 receptor (D2R), where it acts as an antagonist (Dyhring et al. 2010; Sahlholm et al. 2014) or very weak partial agonist (Seeman et al. 2009; Kara et al. 2010). P r i d o p i d i n e a n t a g o n i z e s a m p h e t a m i n e - i n d u c e d hyperlocomotion (Natesan et al. 2006; Ponten et al. 2010) and reduces L-DOPA-induced locomotor sensitization in 6hydroxydopamine-lesioned rats (Ponten et al. 2013). However, even at doses resulting in near-complete D2R occupancy (assessed using ex vivo radioligand binding), pridopidine shows very low propensity for inducing catalepsy (Natesan et al. 2006). Furthermore, pridopidine stimulates locomotor activity in habituated animals showing low baseline locomotor activity (Rung et al. 2008) and increases dopamine release in several brain regions including the prefrontal cortex (Ponten et al. 2010). Based on these properties, pridopidine and structurally related compounds showing similar in vivo efficacy such as (−)-OSU6162 have been termed Bdopamine stabilizers^ as they exhibit inhibitory or stimulatory effects on dopamine-dependent behavior depending on the prevailing dopamine tone (Ponten et al. 2010). (−)-OSU6162 displays higher in vitro affinity for D2R than pridopidine (Pettersson et al. 2010). Interestingly however, while (−)-OSU6162 was more potent in raising serum prolactin and in producing D2R occupancy, pridopidine was more potent in inhibiting amphetamine-induced hyperlocomotion (Natesan et al. 2006). Moreover, pridopidine showed procognitive and pro-social effects, which are not typical of D2R ligands, in animal models of cognitive and negative symptoms of schizophrenia and in scopolamine-induced amnesia (Rung et al. 2005; Nilsson and Carlsson 2013). Furthermore, the abilities of haloperidol and (−)-OSU6162 to counteract amphetamine-induced hyperlocomotion were abolished in D2R knockout mice, whereas the effects of pridopidine persisted (Svensson et al. 2009). Based on the induction of the immediate-early gene Arc (a marker of synaptic activity) by pridopidine in prefrontal cortex, which again is not obs e r v e d w i t h o t h e r D 2 R a n t a g o n i s t s o r a g o n i s t s , nondopaminergic effects of pridopidine have been postulated, which would involve an increase in cortical N-methyl-D-aspartate (NMDA) receptor activity (Ponten et al. 2010; Waters et al. 2014). Finally, neuroprotective effects of pridopidine and (−)-OSU6162 have recently been described in in vitro and in vivo models of Huntington’s disease (Ruiz et al. 2012; DiPardo et al. 2013). T (...truncated)


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Kristoffer Sahlholm, Jurgen W. A. Sijbesma, Bram Maas, Chantal Kwizera, Daniel Marcellino, Nisha K. Ramakrishnan, Rudi A. J. O. Dierckx, Philip H. Elsinga, Aren van Waarde. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses, Psychopharmacology, 2015, pp. 3443-3453, Volume 232, Issue 18, DOI: 10.1007/s00213-015-3997-8