Application of the PET ligand [ 11 C]ORM-13070 to examine receptor occupancy by the α 2C -adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

Background: Availability of the α _2C -adrenoceptor (α _2C -AR) positron emission tomography (PET) tracer, [ ¹¹ C]ORM-13070, and the α _2C -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 [ ¹¹ C]ORM-13070 autoradiography and PET to determine α _2C -AR occupancy by ORM-12741 in rat and human brain, respectively.
Results: ORM-12741 has high affinity (K _i : 0.08 nM) and potent antagonist activity (K _b : 0.04 nM) as well as selectivity (K _i estimates for the human α _2A -AR and α _2B -AR were 8.3 nM and 0.8 nM, respectively) for the human α _2C -AR subtype. [ ¹¹ C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [ ¹¹ C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC ₅₀ 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 α _2C -AR occupancy was detected with EC ₅₀ 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 α _2C -AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively.
Conclusions: ORM-12741 is a selective α _2C -AR antagonist which penetrates the rat and human brain to occupy α _2C -ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .