Evaluation of iodinated and brominated [11C]styrylxanthine derivatives asin vivo radioligands mapping adenosine A2A receptor in the central nervous system

In vivo assessment of the adenosine A2A receptors localized in the striatum by PET or SPECT offers us a new diagnostic tool for neurological disorders. In the present study, we evaluated the potential of iodinated and brominated styrylxanthine derivatives labeled with 11C as an in vivo probe. 7-Methyl-11C]-(E)-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxan thine (11C]IS-DMPX) and 7-methyl-11C]-(E)-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxa nthine (11C]BS-DMPX) were prepared by the 11C-methylation of corresponding 7-demethyl derivatives. An in vitro membrane binding study showed a high affinity (Ki values) of the two ligands for A2A receptor: 8.9 nM for IS-DMPX and 7.7 nM for BS-DMPX, and a high A2A/A1 selectivity: > 1100 for IS-DMPX and 300 for BS-DMPX. In mice, 11C]IS-DMPX and 11C]BS-DMPX were taken up slightly more in the striatum than in the reference regions such as the cortex and cerebellum. The uptake ratios of striatum to cortex and striatum to cerebellum gradually increased but were very small: 1.6-1.7 for the striatum-to-cortex ratio and 1.2 for the striatum-to-cerebellum ratio at 60 min postinjection. The uptake by these three regions was reduced by co-injection of an excess amount of carrier or an A2A antagonist KF17837, but not by an A1 antagonist KF15372. The blocking effects in the three regions were greater for 11C]BS-DMPX (32-57%) than for 11C]IS-DMPX (6-29%). Ex vivo autoradiography confirmed that the two ligands were slightly concentrated in the striatum. 11C]BS-DMPX showed more selective affinity for adenosine A2A receptors than 11C]IS-DMPX, but these results have shown that the two tracers were not suitable as in vivo ligands because of low selectivity for the striatal A2A receptors and a high nonspecific binding.