Document Detail


Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain.
MedLine Citation:
PMID:  18566974     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adenosine A(2A) receptors are found on striatal neurones projecting to the external pallidum. KW-6002 (istradefylline) is a potent and selective antagonist for the adenosine A(2A) receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [(11)C]KW-6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW-6002 at varying doses in human. The highest [(11)C]KW-6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [(11)C]KW-6002 uptake was well characterized in humans by a two-tissue compartmental model with a blood volume term, and the ED(50) of cold KW-6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A(2A) receptors. MRS 1745, an A(2B) receptor selective antagonist, had no effect on the cerebellar binding of [(11)C]KW-6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A(2B) receptors.
Authors:
D J Brooks; M Doder; S Osman; S K Luthra; E Hirani; S Hume; H Kase; J Kilborn; S Martindill; A Mori
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial    
Journal Detail:
Title:  Synapse (New York, N.Y.)     Volume:  62     ISSN:  0887-4476     ISO Abbreviation:  Synapse     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-07-15     Completed Date:  2008-09-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8806914     Medline TA:  Synapse     Country:  United States    
Other Details:
Languages:  eng     Pagination:  671-81     Citation Subset:  IM    
Copyright Information:
Published 2008 Wiley-Liss, Inc.
Affiliation:
MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, London, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adult
Animals
Carbon Radioisotopes / diagnostic use
Cerebellum / metabolism,  radionuclide imaging
Cerebral Cortex / metabolism,  radionuclide imaging
Dose-Response Relationship, Drug
Humans
Kinetics
Male
Middle Aged
Neostriatum / metabolism*,  radionuclide imaging*
Nucleus Accumbens / metabolism,  radionuclide imaging
Positron-Emission Tomography / methods*
Purines / administration & dosage,  diagnostic use*
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-2 / antagonists & inhibitors,  metabolism*
Thalamus / metabolism,  radionuclide imaging
Chemical
Reg. No./Substance:
0/Carbon Radioisotopes; 0/Purines; 0/Receptors, Adrenergic, alpha-2; 0/receptor, adrenergic, alpha-2A; 155270-99-8/istradefylline

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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