Imaging in Central Nervous System Drug Discovery

Gunn, Roger N.; Rabiner, Eugenii A.

doi:10.1053/j.semnuclmed.2016.09.001

Cited by 41 publications

(40 citation statements)

References 58 publications

(58 reference statements)

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“…where Occ max denotes the predicted highest attainable occupancy, C P is plasma psilocin concentration and EC 50 is the plasma psilocin concentration at 50% Occ max (Gunn and Rabiner, 2017) Modelling and curve fitting was performed in GraphPad Prism.…”

Section: Discussionmentioning

confidence: 99%

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Madsen

Fisher

Burmester

et al. 2019

Neuropsychopharmacol.

317

306

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The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin's active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans.Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [ 11 C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3-30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modelled using non-linear regression.Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores.We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin timeconcentration curves varied but psilocin levels were closely associated with psychedelic experience.

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Section: Discussionmentioning

confidence: 99%

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Madsen

Fisher

Burmester

et al. 2019

Neuropsychopharmacol.

317

306

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show abstract

“…Such studies in the living human brain are of unmet need since in vitro data might not necessarily reflect the true functional levels or might differ by orders of magnitude in their affinities from what we see in vivo . An extended quantitative description of drug properties in vivo including tissue exposure, target engagement, and pharmacological activity 121 , molecular neuroimaging with simultaneous PET/fMRI will increasingly be part of the central nervous system drug-development process (from preclinical studies to clinical trials), thereby reducing sample sizes, associated costs and risks of these studies.…”

Section: Multi-modal Imaging Of Receptor Functional Dynamics Witmentioning

confidence: 99%

News and views on in-vivo imaging of neurotransmission using PET and MRI

Sander

Hesse

2017

Q J Nucl Med Mol Imaging

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“…This has been a widely used strategy in recent years where demonstrating the level of target engagement can inform the subsequent therapeutic dose selected [8,9]. Most target engagement studies have been conducted in the central nervous system (CNS), where PET has been the only way to acquire such information [10,11]. Once radiochemistry methods have been established, these studies are operationally straightforward and the occupancy-exposure relationship can be measured using small numbers of healthy volunteers at a single centre.…”

Section: (Ii) Target Engagementmentioning

confidence: 99%

Has molecular imaging delivered to drug development?

Murphy

Patel

McCarthy

2017

Phil. Trans. R. Soc. A.

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Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

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Imaging in Central Nervous System Drug Discovery

Cited by 41 publications

References 58 publications

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

News and views on in-vivo imaging of neurotransmission using PET and MRI

Has molecular imaging delivered to drug development?

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