Synthesis, radiolabeling and preclinical evaluation of a [ 11 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 [11 C]GMOM ([11 C]1) as the lead compound.

METHODS: [11 C]1, its fluoralkyl analogue [18 F]PK209 ([18 F]2) and the newly synthesized fluorovinyloxy analogue [11 C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11 C]7b was subjected to a biodistribution study and its affinity (Ki ) and lipophilicity (logD7.4 ) values were determined.

RESULTS: The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11 C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11 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 [11 C]1, [18 F]2 and [11 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 [18 F]2 and [11 C]7b then for [11 C]1, although differences were not significant. At 45min, significantly more parent [18 F]2 and [11 C]7b was measured in the brain compared with [11 C]1.