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/.