Synthesis, radiolabeling and preclinical evaluation of a [¹¹C]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 [¹¹C]GMOM ([¹¹C]1) as the lead compound. Methods [¹¹C]1, its fluoralkyl analogue [¹⁸F]PK209 ([¹⁸F]2) and the newly synthesized fluorovinyloxy analogue [¹¹C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [¹¹C]7b was subjected to a biodistribution study and its affinity (K_i) and lipophilicity (logD_7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [¹¹C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [¹¹C]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. 45 min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [¹¹C]1, [¹⁸F]2 and [¹¹C]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 [¹⁸F]2 and [¹¹C]7b then for [¹¹C]1, although differences were not significant. At 45 min, significantly more parent [¹⁸F]2 and [¹¹C]7b was measured in the brain compared with [¹¹C]1.