Synthesis, radiolabeling and preclinical evaluation of a [C]GMOM derivative as PET radiotracer for the ion channel of the N-methyl-D-aspartate receptor.

INTRODUCTION

Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [C]GMOM ([C]1) as the lead compound.

METHODS

[C]1, its fluoralkyl analogue [F]PK209 ([F]2) and the newly synthesized fluorovinyloxy analogue [C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [C]7b was subjected to a biodistribution study and its affinity (K) and lipophilicity (logD) values were determined.

RESULTS

The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [C]1, [F]2 and [C]7b, respectively. In plasma, 26-31% of activity was due to parent compound.

CONCLUSION

Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [F]2 and [C]7b then for [C]1, although differences were not significant. At 45min, significantly more parent [F]2 and [C]7b was measured in the brain compared with [C]1.