Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats.

Abstract

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D2/D3 agonist/H3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [11C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [11C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (VT) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the VT values of [11C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D2/D3 receptors and an antagonist at histamine H3 receptors could be demonstrated in the rat brain with [11C]raclopride and [11C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D2/D3 and moderate (submicromolar) affinity to H3 receptors.

• Authors: Nafiseh Ghazanfari, Aren van Waarde, Janine Doorduin, Jürgen W A Sijbesma, Maria Kominia, Martin Koelewijn, Khaled Attia, David Vállez-García, Antoon T M Willemsen, André Heeres, Rudi A J O Dierckx, Ton J Visser, Erik F J de Vries, Philip H Elsinga
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 19 Issue 7 Pg. 2287-2298 (07 04 2022) ISSN: 1543-8392 [Electronic] United States
• PMID: 35732005 (Publication Type: Journal Article)

Chemical References

• Ligands
• Pharmaceutical Preparations
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Raclopride
• Histamine
• Dopamine

Topics

• Animals
• Brain (diagnostic imaging, metabolism)
• Dopamine
• Histamine (metabolism)
• Ligands
• Male
• Mammals (metabolism)
• Pharmaceutical Preparations (metabolism)
• Positron-Emission Tomography (methods)
• Raclopride
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (metabolism)
• Receptors, Dopamine D3 (metabolism)