Dataset Information

Application of the PET ligand [¹¹C]ORM-13070 to examine receptor occupancy by the ?_2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

ABSTRACT:

Background

Availability of the ?_2C-adrenoceptor (?_2C-AR) positron emission tomography (PET) tracer, [¹¹C]ORM-13070, and the ?_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 [¹¹C]ORM-13070 autoradiography and PET to determine ?_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 ?_2A-AR and ?_2B-AR were 8.3 nM and 0.8 nM, respectively) for the human ?_2C-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 ?_2C-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 ?_2C-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively.

Conclusions

ORM-12741 is a selective ?_2C-AR antagonist which penetrates the rat and human brain to occupy ?_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/ .

SUBMITTER: Shahid M

PROVIDER: S-EPMC7726058 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Application of the PET ligand [11C]ORM-13070 to examine receptor occupancy by the α2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

Shahid Mohammed M Rinne Juha O JO Scheinin Mika M Virta Jere J Marjamäki Päivi P Solin Olof O Arponen Eveliina E Sallinen Jukka J Kuokkanen Katja K Rouru Juha J

EJNMMI research 20201209 1

<h4>Background</h4>Availability 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 ...[more]

PMID: 33296042

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Project description:Adenosine A2A and dopamine D2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A2A receptor-mediated modulation of D2 receptor binding in vivo using positron emission tomography (PET) with the D2 antagonist tracer [11C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [11C]raclopride at baseline and 7 days later following an acute administration of the A2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BPND) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [11C]raclopride BPND (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BPND from the k3/k4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [11C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k3/k4 ratio (p < 0.01), but k3 and k4 estimates may be less reliable. The BPND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A2A agonist CGS21680, but not the antagonist KW6002, may reduce the D2 receptor availability in the striatum.

Dataset Information

Application of the PET ligand [¹¹C]ORM-13070 to examine receptor occupancy by the ?_2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

Background

Results

Conclusions

Publications

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

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Dataset Information

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

Background

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Application of the PET ligand [¹¹C]ORM-13070 to examine receptor occupancy by the ?_2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.