A human PET study of [11C]HMS011, a potential radioligand for AMPA receptors

Keisuke Takahata,Chie Seki,Tetsuya Suhara,Kazunori Kawamura,Tatsuya Ishii,Yoko Ikoma,Makoto Higuchi,Masanori Ichise,Manabu Kubota,Yuhei Takado,Sho Moriguchi,Soichiro Kitamura,Yasuyuki Kimura,Tomohisa Nagashima,Masaki Tokunaga,Fumitoshi Niwa,Maiko Ono,Hironobu Endo,Ming-Rong Zhang

doi:10.1186/s13550-017-0313-0

Abstract

Backgroundα-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics.Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (VTs) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference.ResultsBrain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in the brain.ConclusionsKinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

Highlights

Glutamate is the major excitatory neurotransmitter in the central nervous system
We developed a derivative of perampanel, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011), as a positron emission tomography (PET) ligand for αAmino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors
We found small Binding potential (BP*ND) values in the cerebral cortical regions, indicating the specific binding components for [11C]HMS011 in the human brain. These results indicated that reference tissue models using the white matter as reference tissue can be useful for quantification of AMPA receptors; this methodology will need to be validated using PET ligands for AMPA receptors with higher amounts of specific binding than [11C]HMS011

Summary

Introduction

Glutamate is the major excitatory neurotransmitter in the central nervous system. Αamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are largely located in the postsynaptic membrane in the cerebral cortex [1] and mediate fast excitatory signaling within the central nervous system. Animal and human studies have implicated AMPA receptors in a wide range of brain disorders, including epilepsy [2], amyotrophic lateral sclerosis [3], mood disorders [4], and schizophrenia [5]. A non-invasive method to visualize the density and distribution of AMPA receptors in the human brain would be a critical step for understanding the mechanisms underlying these neuropsychiatric disorders. While considerable efforts have been made to develop PET ligands for other glutamate receptors such as the Nmethyl-D-aspartate (NMDA) receptor family, AMPA receptor imaging has remained largely unexplored. A prototypical competitive AMPA receptor antagonist, 2,3dihydroxy-6-nitro-7-sulfamoyl-benzo(f )quinoxaline (NBQX), demonstrated significant anticonvulsant effects [6], its clinical use has been prevented by its neurotoxicity and poor penetration of the blood-brain barrier [7]

Methods

Results

Discussion

Conclusion