Translational possibility of [ F]Mefway to image serotonin 1A receptors in humans: Comparison with [ F]FCWAY in rodents.

PURPOSE

To compare the cerebral uptake and binding potential of [ F]FCWAY and [ F]Mefway in the rodent to assess their potential for imaging serotonin 1A (5-HT ) 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 anti-defluorination agent. The regions of interest were the hippocampus and frontal cortex (5-HT target regions) and the cerebellum (5-HT 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 ) as a steady-state binding parameter. Finally, binding affinities to 5-HT receptors were assessed in Chinese hamster ovary cells (CHO-K1) cells expressing human recombinant 5-HT receptors.

RESULTS

The radiochemical yield of [ F]Mefway was slightly higher than that of [ F]FCWAY (19 vs. 15%). With regard to metabolic stability against defluorination, both compounds exhibited similar stability in rat liver microsomes, but [ 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 [ F]Mefway and [ F]FCWAY, respectively). There were no significant differences in brain uptake, the target-to-nontarget ratios, and the BP (at hippocampus, peak brain uptakes: 6.9 vs. 8.5, target-to-nontarget ratios: 6.9 vs. 8.5, BP : 5.2 vs. 6.2 for [ F]Mefway and [ F]FCWAY). The binding affinity of [ F]Mefway was considerably higher than that of [ F]FCWAY (IC : 1.5 nM vs. 2.2 nM).

CONCLUSION

[ F]Mefway exhibits favorable characteristics compared to [ F]FCWAY in rodents, and may be a promising radioligand for use in human subjects. Synapse 68:595-603, 2014. © 2014 Wiley Periodicals, Inc.