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

K. Ishibashi,Yoshiharu Miura,K. Wagatsuma,J. Toyohara,K. Ishiwata,K. Ishii

Published 2018 in Neuropharmacology

ABSTRACT

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 20mg or 40mg, 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 20mg or 40mg (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 28.6mg in the ventral striatum, 69.5% and 10.8mg in the caudate, and 66.8% and 14.8mg 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. HIGHLIGHTSIstradefylline is an adenosine A2A receptor (A2AR) antagonist, effective in PD.We calculated occupancy rates of A2ARs by istradefylline 20mg or 40mg.ED50 value was 14.8mg in the striatum.Sufficient occupancy is obtained by the approved doses: 20mg or 40mg.

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