Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2534147 | European Journal of Pharmacology | 2009 | 8 Pages |
Abstract
The adenosine A2A receptor in the basal ganglia is involved in the control of movement and plays a role in movement disorders such as Parkinsonism. Developing ligands to evaluate that receptor by noninvasive methods such as positron emission tomography has a high priority. In vitro radioligand binding guides the selection of ligands for in vivo application. This study measured the binding of the adenosine A2A receptor antagonist [3H]MSX-2 (3-(3-hydroxypropyl)-8-m-methoxystyryl)-7-methyl-1-propargylxanthine) to rat, mouse and pig brain by autoradiography. Other studies measured binding to membranes from PC12 pheochromocytoma cells. Those binding parameters were compared to those of the adenosine A2A receptor antagonist [3H]ZM241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino)ethyl)phenol), the adenosine A2A receptor agonist [3H]CGS21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5â²-N-ethylcarboxamidoadenosine) and the unselective adenosine receptor agonist [3H]NECA (5â²N-ethylcarboxamido)adenosine). The potency order (Kd) in the three species was [3H]ZM241385Â <Â [3H]MSX-2Â <Â [3H]NECAÂ <Â [3H]CGS21680. The density of [3H]MSX-2 binding sites was greater in the striatum than in the cortex. Preliminary ex vivo experiments showed that by 10Â min after iv injection, [3H]MSX-2 and [3H]CGS21680 crossed the blood-brain barrier to the extent of almost 1% ID/g brain tissue, but [3H]NECA and [3H]ZM241385 to only 0.2% ID/g. The prior administration of unlabeled ZM241385 significantly lowered brain uptake of [3H]MSX-2. In conclusion, [3H]MSX-2 has a high affinity and sufficient selectivity for the adenosine A2A receptor. It penetrates the blood-brain barrier. Sensitivity to photoisomerization is a limitation. Further investigations assess its suitability as a ligand for imaging the brain adenosine A2A receptor.
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Authors
Wiebke Sihver, Annette Schulze, Walter Wutz, Stefan Stüsgen, Ray A. Olsson, Dirk Bier, Marcus H. Holschbach,