Abstract
BackgroundAvailability of the α2C-adrenoceptor (α2C-AR) positron emission tomography (PET) tracer, [11C]ORM-13070, and the α2C-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [11C]ORM-13070 autoradiography and PET to determine α2C-AR occupancy by ORM-12741 in rat and human brain, respectively.ResultsORM-12741 has high affinity (Ki: 0.08 nM) and potent antagonist activity (Kb: 0.04 nM) as well as selectivity (Ki estimates for the human α2A-AR and α2B-AR were 8.3 nM and 0.8 nM, respectively) for the human α2C-AR subtype. [11C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [11C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α2C-AR occupancy was detected with EC50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α2C-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively.ConclusionsORM-12741 is a selective α2C-AR antagonist which penetrates the rat and human brain to occupy α2C-ARs in a manner consistent with its receptor pharmacology.Trialregistrationnumberanddateofregistration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/.
Highlights
Availability of the α2C-adrenoceptor (α2C-AR) positron emission tomography (PET) tracer, [11C]ORM13070, and the α2C-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders
Direct evidence supporting drug target engagement is a key element for establishing confidence in proof of concept evaluation in nonclinical and human studies [3]. [11C]ORM-13070 as a PET tracer has provided a valuable probe for investigating α2C-AR subtype functions as well as brain receptor occupancy in experimental animals and humans
The Inhibition constant (Ki) estimates for the human α2A-AR, α2B-AR and α2C-AR were 8.3, 0.8 and 0.08 nM, respectively
Summary
Availability of the α2C-adrenoceptor (α2C-AR) positron emission tomography (PET) tracer, [11C]ORM13070, and the α2C-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. Results obtained with gene-targeted (knock-out) mice indicate that manipulation of α2A-AR and α2C-AR activation yields differential behavioural effects in nonclinical tests that are commonly used for assessing antidepressant, antipsychotic or pro-cognitive properties of drugs [1]. This has led to the proposition that selective α2C-AR antagonism might be a promising approach for the treatment of neuropsychiatric symptoms, potentially across a wide range of CNS disorders, with an improved therapeutic profile compared to nonselective α2-AR antagonists [1]. Additional work has shown that [11C]ORM-13070 binding is sensitive to changes in extracellular NA concentrations in the human brain, provoked by physiological or pharmacological interventions, indicating that it may be a valuable tracer for the investigation of alterations in noradrenergic tone [8, 9]
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