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

Abstract

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.

Recent developments in adenosine receptor ligands and their potential as novel drugs

“…11 C labeled ( E )-8-(3-chlorostyryl)-1,3-dimethyl-7-[ 11 C]methylxanthine ([ 11 C]CSC, 50 ) proved to accumulate in the striatum, and PET studies on rabbits showed a fast brain uptake of [ 11 C]CSC, reaching a maximum in less than 2 min [122]. Further styrylxanthine derivatives labeled with 11 C were tested as in vivo probes [123]. [7-Methyl- 11 C]-( E )-3,7-dimethyl-8-(3-iodostyryl)-1-pro-pargylxanthine ([ 11 C]IS-DMPX, 91 ) and [7-methyl- 11 C]-( E )-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine ([ 11 C]BS-DMPX, 92 ) showed K i affinities of 8.9 and 7.7 nM respectively, and high A 2A /A 1 selectivity values.…”

“…[7-Methyl- 11 C]-( E )-3,7-dimethyl-8-(3-iodostyryl)-1-pro-pargylxanthine ([ 11 C]IS-DMPX, 91 ) and [7-methyl- 11 C]-( E )-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine ([ 11 C]BS-DMPX, 92 ) showed K i affinities of 8.9 and 7.7 nM respectively, and high A 2A /A 1 selectivity values. Unfortunately, biological studies proved that the two ligands were only slightly concentrated in the striatum, and that the two compounds were not suitable as in vivo ligands because of low selectivity for the striatal A 2A receptors and a high degree of nonspecific binding [123]. A useful A 2A PET ligand for in vivo imaging proved to be [ 11 C]KF18446 ( 93 ), also named ( 11 C)TMSX [124].…”

Xanthines as Adenosine Receptor Antagonists

“…This molecule was shown to accumulate in the striatum, and PET studies on rabbits showed a fast brain uptake of [ 11 C]CSC, reaching a maximum in less than 2 min (Marian et al 1999). Few years later, iodinated and brominated styrylxanthine derivatives labeled with 11 C were tested as in vivo probes (Ishiwata et al 2000c). [7-Methyl- 11 C]-( E )-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxanthine ([ 11 C]IS-DMPX) and [7-methyl- 11 C]-( E )-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine ([ 11 C]BS-DMPX) showed K i affinities of 8.9 and 7.7 nM respectively, and high A 2A /A 1 selectivity values.…”

“…[7-Methyl- 11 C]-( E )-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxanthine ([ 11 C]IS-DMPX) and [7-methyl- 11 C]-( E )-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthine ([ 11 C]BS-DMPX) showed K i affinities of 8.9 and 7.7 nM respectively, and high A 2A /A 1 selectivity values. Unfortunately, biological studies proved that the two ligands were only slightly concentrated in the striatum, and that they were not suitable as in vivo ligands because of low selectivity for the striatal A 2A receptors and a high nonspecific binding (Ishiwata et al 2000c). …”

The Adenosinergic System

“…Further investigation of [ 11 C]KF17837 showed this radiotracer had poor selectivity for A 2A , as additional binding sites were subsequently identified. However, despite the good in vitro affinity and selectivity for A 2A , [ 11 C]IS-DMPX and [ 11 C]BS-DMPX displayed high nonspecific binding and limited selectivity for the target in vivo, indicating that these radiotracers were not suitable for imaging of A 2A in brain (Ishiwata et al 2000d). These radiotracers had similar properties to [ 11 C] KF17837 and thus, were deemed unsuitable for in vivo imaging of A 2A receptors in brain ).…”