Translational Possibility of [~(18)F]Mefway to Image Serotonin 1A Receptors in Humans: Comparison With [~(18)F]FCWAY in Rodents

摘要

Purpose: To compare the cerebral uptake and binding potential of [~(18)F]FCWAY and [~(18)F]Mefway in the rodent to assess their potential for imaging serotonin 1A (5-HT1A) receptors. Materials and Methods: In vitro liver microsomal studies were performed to evaluate the degree of defluorination. Dynamic positron emission tomography (PET) studies were then conducted for 2 h with or without an antidefluorination agent. The regions of interest were the hippocampus and frontal cortex (5-HT1A target regions) and the cerebellum (5-HT1A nontarget region). The in vivo kinetics of the radioligands were compared based on the brain uptake values and target-to-nontarget ratio. We also performed a comparison of binding potential (BP_(ND)) as a steady-state binding parameter. Finally, binding affinities to 5-HT1A receptors were assessed in Chinese hamster ovary cells (CHO-K1) cells expressing human recombinant 5-HT1A receptors. Results: The radiochemical yield of [~(18)F]Mefway was slightly higher than that of [~(18)F]FCWAY (19 vs. 15%). With regard to metabolic stability against defluorination, both compounds exhibited similar stability in rat liver microsomes, but [~(18)F]Mefway displayed higher stability in the human microsome (defluorination ratio at 30 min: 32 vs. 29 in rat liver microsomes, 31 vs. 64 in human liver microsomes for [~(18)F]Mefway and [~(18)F]FCWAY, respectively). There were no significant differences in brain uptake, the target-to-nontarget ratios, and the BP_(ND) (at hippocampus, peak brain uptakes: 6.9 vs. 8.5, target-to-nontarget ratios: 6.9 vs. 8.5, BP_(ND): 5.2 vs. 6.2 for [~(18)F]Mefway and [~(18)F]FCWAY). The binding affinity of [~(18)F]Mefway was considerably higher than that of [~(18)F]FCWAY (IC50: 1.5 nM vs. 2.2 nM). Conclusion: [~(18)F]Mefway exhibits favorable characteristics compared to [~(18)F]FCWAY in rodents, and may be a promising radioligand for use in human subjects.