Translational possibility of [18 F]Mefway to image serotonin 1A receptors in humans: Comparison with [18 F]FCWAY in rodents

Jae Yong Choi; Byoung Soo Kim; Chul Hoon Kim; Dong Goo Kim; Sang Jin Han; Kyochul Lee; Kyeong Min Kim; Gwangil An; Tae Hyun Choi; Sun Dong Yoo; Young Hoon Ryu

doi:10.1002/syn.21771

Translational possibility of [¹⁸ F]Mefway to image serotonin 1A receptors in humans: Comparison with [¹⁸ F]FCWAY in rodents

Synapse. 2014 Dec;68(12):595-603. doi: 10.1002/syn.21771. Epub 2014 Jul 31.

Authors

Affiliations

¹ Department of Nuclear Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, 135-720, Korea.
² Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Korea.
³ Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Korea.
⁴ College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Korea.

PMID: 25056144
DOI: 10.1002/syn.21771

Abstract

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-HT_1A ) 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_1A target regions) and the cerebellum (5-HT_1A 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-HT_1A receptors were assessed in Chinese hamster ovary cells (CHO-K1) cells expressing human recombinant 5-HT_1A 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. Synapse 68:595-603, 2014. © 2014 Wiley Periodicals, Inc.

Keywords: [18F]FCWAY; [18F]Mefway; microPET; serotonin 1A receptors.