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

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

2017-08 , Springer Berlin
Background: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fastglutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. Werecently 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 ofperampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivoproperties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011to evaluate its safety and kinetics.Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood samplingand metabolite analysis were performed to obtain parent input functions for three of the subjects using highperformanceliquid chromatography. Regional distribution volumes (VTs) were calculated based on kinetic modelswith and without considering radiometabolite in the brain. The binding was also quantified using a reference tissuemodel with white matter as reference.Results: Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Threehydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kineticsin the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. Adual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, welldescribed 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 inthe brain.Conclusions: Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligandmay not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.Keywords: PET, Perampanel, AMPA, [11C]HMS011, Interspecies differences

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