Evaluation of iodinated and brominated [C-11]styrylxanthine derivatives asin vivo radioligands mapping adenosine A(2A) receptor in the central nervous system

In vivo assessment of the adenosine A(2A) receptors localized in the striat um by PET or SPECT offers us a new diagnostic tool for neurological disorde rs. In the present study, we evaluated the potential of iodinated and bromi nated styrylxanthine derivatives labeled with C-11 as an in vivo probe. [7- Methyl-C-11]-(E)-3,7-dimethyl-8-(3-icrdostyryl)-1-propargylxanthine ([C-11] IS-DMPX) and [7-methyl-C-11]-(E)-8-(3-bromostyryl) 3,7-dimethyl-[C-11]-(E)- 8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine ([C-11]BS-DMPX) were pre pared by the C-11-methylation of corresponding 7-demethyl derivatives. An i n vitro membrane binding study showed a high affinity (Ki values) of the tw o ligands for A2A receptor: 8.9 nM for IS-DMPX and 7.7 nM for BS-DMPX, and a high A(2A)/A(I) selectivity: >1100 for IS-DMPX and 300 for BS-DMPX. In mi ce, [C-11]IS-DMPX and [C-11]BS-DMPX were taken up slightly more in the stri atum than in the reference regions such as the cortex and cerebellum. The u ptake ratios of striatum to cortex and striatum to cerebellum gradually inc reased 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 c arrier or an A(2A) antagonist KF17837, but not by an Al antagonist KF15372. The blocking effects in the three regions were greater for [C-11]BS-DMPX ( 32-57%) than for [C-11]IS-DMPX (6-29%). Ex vivo autoradiography confirmed t hat the two ligands were slightly concentrated in the striatum. [C-11]BS-DM PX showed more selective affinity for adenosine A(2A) receptors than [C-11] IS-DMPX, but these results have shown that the two tracers were not suitabl e as in vivo ligands because of low selectivity for the striatal A(2A) rece ptors and a high nonspecific binding.