Preladenant, a selective A 2A receptor antagonist, is active in primate models of movement disorders Robert A. Hodgson a, ⁎, Paul J. Bedard b , Geoffrey B. Varty a , Tatiana M. Kazdoba a , Therese Di Paolo c , Michael E. Grzelak a , Annamarie J. Pond a , Abdallah HadjTahar b , Nancy Belanger b , Laurent Gregoire b,c , Aurelie Dare b , Bernard R. Neustadt d , Andrew W. Stamford d , John C. Hunter e a Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA b Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University, Quebec, Canada c Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), Quebec, Canada d Department of Chemical Research, Merck and Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA e Department of Neurobiology, Merck and Co. Inc. 770 Sumneytown Pike, West Point, PA 19486, USA abstract article info Article history: Received 3 June 2010 Revised 14 July 2010 Accepted 15 July 2010 Available online 23 July 2010 Keywords: Preladenant MPTP Extrapyramidal Syndrome Monkey Parkinson's Disease A 2A Adenosine Movement disorder Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D 2 receptors by antipsychotics, respectively. Adenosine A 2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal (“indirect”) pathway, where they appear to operate in concert with D 2 receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A 2A receptor activation contributes to the overdrive of the indirect pathway. A 2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A 2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A 2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A 2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3–3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic- induced movement disorders. © 2010 Elsevier Inc. All rights reserved. Introduction Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are two movement disorders associated with a decrease of dopaminergic activity. PD is characterized by a progressive loss of the dopaminergic neuronal projection from substantia nigra pars compacta to the striatum. EPS results from chronic inhibition of striatal dopamine D 2 receptors, and is frequently associated with antipsychotic medications such as haloperidol. Acute EPS has a prevalence of up to 90% of patients treated with antipsychotic medications (Casey and Keepers, 1988). The adenosine A 2A receptor is highly localized to enkephali- nergic striatopallidal GABA-ergic neurons of the striatum (Hettinger et al., 2001). These neurons, which receive dopamine input, form part of the indirect pathway of movement, which projects via a relay network substantia nigra reticulata (SNr). The stimulatory A 2A and inhibitory D 2 receptors are colocalized on these neurons where they act in an opposing manner to provide a balanced output of activity. An A 2A receptor antagonist, therefore, can impact the downstream activity of this pathway in a manner that is similar to D 2 receptor agonists, which are commonly used to treat PD. As such, interest has developed in the potential of A 2A receptor antagonists as non- dopaminergic treatments for PD and EPS. Using in vivo microdialysis, Ochi et al. (2004) demonstrated that administration of the A 2A receptor antagonist istradefylline (also referred to as KW-6002) produced an increase in GABA in the SNr in 6-OHDA lesioned rats. In 6-OHDA lesioned rats, istradefylline decreases GABA in the GP, which counters the effect of the lesion on pallidal GABA levels in these animals (Ochi et al., 2000). These findings demonstrate that A 2A receptor manipulation has a controlling influence on GABA output within the indirect pathway and that A 2A Experimental Neurology 225 (2010) 384–390 ⁎ Corresponding author. Fax: +1 908 740 3294. E-mail address: Robert.Hodgson@Merck.com (R.A. Hodgson). 0014-4886/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2010.07.011 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr