Article ID Journal Published Year Pages File Type
2534147 European Journal of Pharmacology 2009 8 Pages PDF
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]-5′-N-ethylcarboxamidoadenosine) and the unselective adenosine receptor agonist [3H]NECA (5′N-ethylcarboxamido)adenosine). The potency order (Kd) in the three species was [3H]ZM241385 < [3H]MSX-2 < [3H]NECA < [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 10 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.
Related Topics
Life Sciences Neuroscience Cellular and Molecular Neuroscience
Authors
, , , , , , ,