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
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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)