Elsevier

Neuropharmacology

Volume 143, December 2018, Pages 106-112
Neuropharmacology

Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson's disease using 11C-preladenant PET

https://doi.org/10.1016/j.neuropharm.2018.09.036Get rights and content

Highlights

  • Istradefylline is an adenosine A2A receptor (A2AR) antagonist, effective in PD.

  • We calculated occupancy rates of A2ARs by istradefylline 20 mg or 40 mg.

  • ED50 value was 14.8 mg in the striatum.

  • Sufficient occupancy is obtained by the approved doses: 20 mg or 40 mg.

Abstract

Istradefylline, an adenosine A2A receptor (A2AR) antagonist, is effective as an adjunct to levodopa and can alleviate “off” time and motor symptoms in patients with Parkinson's disease (PD). The present study aimed to calculate occupancy rates of A2ARs by administrating istradefylline 20 mg or 40 mg, which is the currently approved dose for PD in Japan. Additionally, A2AR availability was compared between patients with PD and healthy controls. Ten patients with PD under levodopa therapy and six age-matched healthy controls were included. The patients underwent a total of two 11C-preladenant positron emission tomography scans before and after the administration of istradefylline 20 mg or 40 mg (both n = 5). Binding potential (BPND) was calculated to estimate A2AR availability in the ventral striatum, caudate, and putamen. Maximal A2AR occupancy and ED50 were estimated by modeling the dose-occupancy curves. All patients were around the middle stage of PD, and their characteristics were clinically heterogeneous. Maximal A2AR occupancy and ED50 were 93.5% and 28.6 mg in the ventral striatum, 69.5% and 10.8 mg in the caudate, and 66.8% and 14.8 mg in the putamen, respectively. There were no significant differences in BPND values in the ventral striatum (P = 0.42), caudate (P = 0.72), and putamen (P = 0.43) between the PD and control groups. In conclusion, the present study shows that istradefylline binds to A2ARs dose-dependently. A sufficient occupancy of A2ARs could be obtained by administrating the approved dose of istradefylline.

Introduction

Adenosine receptors are pharmacologically classified into four subtypes: A1, A2A, A2B, and A3. Adenosine A1, A2B, and A3 receptors are widely distributed in the brain, although the expression of adenosine A2B and A3 receptors is relatively low (Stockwell et al., 2017). Meanwhile, adenosine A2A receptors (A2ARs) are predominantly distributed in the putamen, caudate, nucleus accumbens, and external globus pallidus (Svenningsson et al., 1997). Most A2ARs are located post-synaptically in GABAergic medium spiny neurons in the striatum, which receive afferent input from the substantia nigra pars compacta and project to the external globus pallidus (Mori, 2014a, Pinna et al., 2018). A2ARs are highly expressed in the so-called indirect basal ganglia pathway, but are expressed in very low levels in the direct pathway (Alexander and Crutcher, 1990). Thus, A2ARs can interact with dopamine D2 receptors and play an important role in regulating motor behavior.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and a subsequent loss of dopamine in the striatum, which causes motor symptoms including tremor, rigidity, bradykinesia, and postural instability. In PD, the expression of A2ARs is potentially altered along with progressive dysfunction of the dopaminergic neurotransmission system in the striatum (Mori, 2014b). A human post-mortem study has shown that the expression of A2ARs can be higher in patients with PD who have dyskinesia (Calon et al., 2004). This finding has recently been confirmed in vivo in humans by positron emission tomography (PET) studies using an A2AR radioligand (Mishina et al., 2011, Ramlackhansingh et al., 2011), and these studies also found that the expression of A2ARs can increase after beginning anti-parkinsonian treatment. These findings support the rationale that A2ARs are a therapeutic target in patients with PD, and anti-parkinsonian effects of A2AR antagonists have been shown in rodent models of PD (Jenner et al., 2009, Shiozaki et al., 1999).

Istradefylline, an A2AR antagonist, was launched in Japan in 2013 after several randomized placebo-controlled studies (LeWitt et al., 2008, Mizuno et al., 2010, Mizuno et al., 2013, Pourcher et al., 2012). Since then, meta-analyses have validated that istradefylline is effective as an adjunct to levodopa and can alleviate “off” time and motor symptoms in patients with PD (Chen et al., 2013, Sako et al., 2017, Tao and Liang, 2015). Currently, Japan is the only country where the use of istradefylline in patients with PD has been approved by an official organization. Although once-daily administration of istradefylline 20 mg or 40 mg is recommended, evidence for how many A2ARs are blocked by the administration of these doses in patients with PD is incomplete. The aim of the present study was to calculate occupancy rates of A2ARs by administrating istradefylline 20 mg or 40 mg, which are the currently approved doses for PD in Japan, and to estimate ED50 in patients with PD. For this purpose, we measured A2AR availability using 11C-preladenant PET before and after the administration of istradefylline in patients with PD under anti-parkinsonian treatment with levodopa. Additionally, we compared A2AR availability between patients with PD and healthy controls.

Section snippets

Research participants

The present study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology (H28-49). Written informed consent was obtained from all participants who underwent 11C-preladenant PET and magnetic resonance imaging (MRI) scans. The participants consisted of 10 patients with PD (8 men; aged 74.9 ± 8.2 y [mean ± SD]), and six age-matched volunteers (2 men; aged 76.8 ± 7.1 y). All patients were under medication

Results

The data from the patients with PD are summarized in Table 1, showing that all patients were around the middle stage of PD and that their characteristics were clinically heterogeneous in terms of disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, and medication. There was no significant difference in age (P = 0.81), BSA (P = 0.48), disease duration (P = 0.09), or UPDRS motor scores (P = 0.78) between the low-dose (20 mg) and high-dose (40 mg) groups. Additionally,

Discussion

The primary objective of the present study was to calculate the occupancy rates of A2ARs by istradefylline (administration of 20 mg or 40 mg) and to estimate ED50 in patients with PD under anti-parkinsonian treatment with levodopa. Two variables, dose and dose/BSA, were used for modeling the occupancy curves shown in Fig. 3. As expected, the fitting of curves was better when using dose/BSA as an x-axis variable compared to using dose. However, the maximal occupancy was comparable between the

Conclusions

The present study showed that istradefylline binds to A2ARs in a dose-dependent manner. According to dose-occupancy curves, maximal occupancy and ED50 values were 93.5% and 28.6 mg in the ventral striatum, 69.5% and 10.8 mg in the caudate, and 66.8% and 14.8 mg, in the putamen, respectively, in patients with PD under anti-parkinsonian treatment with levodopa. Sufficient occupancy of A2ARs could be obtained by administrating the approved doses of istradefylline (20 mg or 40 mg).

Conflicts of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This study was funded by Research Grants 2017 of Japan Research Foundation for Clinical Pharmacology (to KIshibashi) and Grant-in-Aid for Scientific Research (B) No. 16H05396 from the Japan Society for the Promotion of Science (to KIshiwata). The authors thank the people of Research Team for Neuroimaging at the Tokyo Metropolitan Institute of Gerontology.

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