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

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 (V Ts) 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-017-0313-0) contains supplementary material, which is available to authorized users.

Synthesis, pharmacology and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein

“…[39–41] PET imaging studies of AMPARs in the living brain would help to obtain insights into excitotoxic conditions and to advance the translational development of AMPAR antagonists via target engagement studies, as well as to enable pharmacokinetic profiling of candidate drug molecules. Despite the fact that several AMPAR PET tracers[42–45] have been developed including [ 11 C]HMS011[46, 47] and our [ 18 F]Perampanel analog, further improvement on target:nonspecific binding ratio is necessary for clinical research (Figure 2A). [47] Furthermore, there is no subtype-selective AMPAR PET tracer (i.e., regulated via specific TARP subgroup) available for drug discovery and translational human imaging studies, despite their advantage of significantly reduced side effects over traditional pan AMPAR antagonists.…”

“…Despite the fact that several AMPAR PET tracers[42–45] have been developed including [ 11 C]HMS011[46, 47] and our [ 18 F]Perampanel analog, further improvement on target:nonspecific binding ratio is necessary for clinical research (Figure 2A). [47] Furthermore, there is no subtype-selective AMPAR PET tracer (i.e., regulated via specific TARP subgroup) available for drug discovery and translational human imaging studies, despite their advantage of significantly reduced side effects over traditional pan AMPAR antagonists. As a result, the unmet clinical need of AMPAR γ−8 selective PET tracers, together with the therapeutic potential of AMPA γ−8 modulating pharmacotherapy, provides a strong stimulus to advance PET tracer development for this target.…”

A Pilot Double‐Blind Randomized Trial of Perampanel for Essential Tremor

“…Alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors are located in several regions within the oscillatory network revealed by magnetoencephalography 4 in ET, including the frontal cerebral and cerebellar cortex. 5 Moreover, AMPA receptors increase the degree of inferior olivary coupling, which in turn increases Purkinje cell complex spike synchrony 6,7 that may be associated with increased movement amplitude and tremor. 6,8 Systemically administered AMPA receptor antagonists suppress tremor in the harmaline animal model, 9,10 whereas PF-4778574, an allosteric AMPA receptor activator, causes tremor in primates and other species.…”

Radiosynthesis of a carbon-11-labeled AMPAR allosteric modulator as a new PET radioligand candidate for imaging of Alzheimer’s disease

“…In this continued effort, we revisit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which is a novel and attractive molecular target for treatment and PET imaging of AD. 14,15 We and other groups have developed several AMPAR PET tracers, [15][16][17][18][19][20][21] and representative radioligands are shown in Figure 2. However, preclinical and clinical evaluation indicated these radioligands have significant drawbacks like not potent enough in vitro IC 50 and/or K i values, low specific binding, high non-specific binding, poor brain entry, inconsistent brain uptake compared to known AMPAR distribution, and small dynamic range and metabolite in the brain.…”

“…However, preclinical and clinical evaluation indicated these radioligands have significant drawbacks like not potent enough in vitro IC 50 and/or K i values, low specific binding, high non-specific binding, poor brain entry, inconsistent brain uptake compared to known AMPAR distribution, and small dynamic range and metabolite in the brain. [15][16][17][18][19][20][21] Thus an ideal AMPAR radioligand that can be used in the clinical setting to study AMPAR expression levels in AD remains to be discovered. Recently a novel series of 7-phenoxysubstituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1dioxides have been developed as positive allosteric modulators of AMPARs with nanomolar potency for potential treatment of AD, and the lead compound, 4cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H- Synthesis of the reference standard 8 and its desmethylated precursor 4-cyclopropyl-7-(3hydroxyphenoxy)-3,4-dihydro-2Hbenzo[e][1,2,4]thiadiazine 1,1-dioxide (9) is outlined in Scheme 1 according to the reported procedures.…”