A first-in-man PET study of [18F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5

Warnock, Geoffrey; Sommerauer, Michael; Mu, Linjing; Gonzalez, Gloria Pla; Geistlich, Susanne; Treyer, Valérie; Schibli, Roger; Buck, Alfred; Krämer, Stefanie-Dorothea; Ametamey, Simon M.

doi:10.1007/s00259-017-3879-x

Cited by 22 publications

(17 citation statements)

References 40 publications

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“…mGluR5 availability was quantified with the novel PET radioligand [ 18 F]PSS232 which is a non-competitive selective antagonist of mGluR5 (Sephton et al, 2014;Warnock et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

“…To quantify sleep-wake associated changes in the availability of mGluR5 that may occur simultaneously with the above described local changes in Glu, GLX and GABA, the newly developed, highly selective, non-competitive mGluR5 antagonist for PET brain imaging, [ 18 F]PSS232, was employed (Sephton et al, 2014;Warnock et al, 2018).…”

Section: Whole-brain Mglur5 Availability Is Elevated After Sleep Deprmentioning

confidence: 99%

“…Tissue Model with fixed k2; (Wu & Carson, 2002)] modelling. For modelling, TACs of receptor-rich regions (gray matter VOIs) were compared to the TAC of a receptor-less region (cerebellum) believed mainly to entail non-specific binding (Warnock et al, 2018).…”

Section: Image Processing and Quantificationmentioning

confidence: 99%

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Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

Weigend

Holst

Treyer

et al. 2018

Preprint

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Both sleep and glutamatergic signaling in the brain are tightly controlled and homeostatically regulated. Sleep homeostasis is reliably reflected by predictable changes in brain electrical activity in waking and sleep, yet the underlying molecular mechanisms remain elusive.Current hypotheses posit that recovery sleep following prolonged waking restores efficient functioning of the brain, for example by keeping glutamatergic signaling in a homeostatic range. We recently provided evidence in humans and mice that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here we combined in 31 healthy men, proton magnetic resonance spectroscopy to measure the levels of glutamate (Glu), GLX (glutamate-to-glutamine ratio) and GABA (γamino-butyric-acid) in basal ganglia (BG) and dorsolateral prefrontal cortex, simultaneous positron emission tomography to quantify mGluR5 availability with the novel radioligand, [ 18 F]PSS232, and quantification in blood plasma of the mGluR5-regulated proteins, fragile-X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF). All measurements were conducted at the same circadian time in baseline, following sleep deprivation and after recovery sleep. We found that Glu and GLX in BG (p all < 0.01), but not in prefrontal cortex, and the plasma concentration of FMRP (p < 0.02), were increased after sleep loss and tended to normalize following recovery sleep (p all < 0.1). Furthermore, a night without sleep enhanced whole-brain and striatal mGluR5 availability and was normalized by recovery sleep (p all < 0.05). By contrast, other brain metabolites and plasma BDNF levels were not altered. The findings demonstrate convergent changes in distinct markers of glutamatergic signaling across prolonged wakefulness and recovery sleep in humans. They warrant further studies to elucidate the underlying mechanisms that link the homeostatic regulation of sleep and glutamatergic system activity in health and disease.

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“…mGluR5 availability was quantified with the novel PET radioligand [ 18 F]PSS232 which is a non-competitive selective antagonist of mGluR5 (Sephton et al, 2014;Warnock et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Section: Whole-brain Mglur5 Availability Is Elevated After Sleep Deprmentioning

confidence: 99%

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Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

Weigend

Holst

Treyer

et al. 2018

Preprint

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“…Ex vivo studies with [ 18 F]PSS232 in rats showed rapid kinetics favorable for evaluation within 70-min PET recordings, despite the presence of some displaceable binding in the cerebellum reference region. The first [ 18 F]PSS232 ( 83 ) study in humans showed well-behaved cerebral kinetics relative to the arterial input function, which was stably quantifiable with dynamic recordings lasting only 45 min [ 204 ]. The considerable metabolic stability of the tracer, which remained 60% intact in plasma samples collected at 90 min after injection, presents a distinct advantage for PET studies with this tracer.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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“…PET allows generating well-defined tissue radioactivity concentration time curves ( C ( t )) from image data. In addition, blood can be sampled to measure the blood C ( t ) simultaneously [ 13 , 14 ]. PET kinetic modelling is a standard method for the quantification of brain function, for example, glucose consumption or neuroreceptor density in preclinical and clinical imaging [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

Taddio

Keller

et al. 2018

Contrast Media & Molecular Imaging

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Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [11C]AM7 and [11C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([11C]AM7 n = 2; [11C]MT107, n = 4) and after administration of cyclosporine ([11C]MT107, n = 4). The modelling revealed a significant reduction in [11C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 μl/min after cyclosporine administration. The excretion profile of [11C]MT107 was shifted from predominantly hepatobiliary (CLH/CLR = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CLH/CLR = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

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A first-in-man PET study of [18F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5

Cited by 22 publications

References 40 publications

Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle

A Review of Molecular Imaging of Glutamate Receptors

Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

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