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

被引：1

作者：

Ghazanfari, Nafiseh ^{[1
]}

van Waarde, Aren ^{[1
]}

Doorduin, Janine ^{[1
]}

Sijbesma, Jurgen W. A. ^{[1
]}

Kominia, Maria ^{[1
]}

Koelewijn, Martin ^{[2
]}

Attia, Khaled ^{[1
]}

Vallez-Garcia, David ^{[1
]}

Willemsen, Antoon T. M. ^{[1
]}

Heeres, Andre ^{[2
]}

Dierckx, Rudi A. J. O. ^{[1
]}

Visser, Ton J. ^{[2
]}

de Vries, Erik F. J. ^{[1
]}

Elsinga, Philip H. ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, NL-9713 GZ Groningen, Netherlands

[2] Symeres BV, NL-9747 AT Groningen, Netherlands

来源：

MOLECULAR PHARMACEUTICS | 2022年

关键词：

Parkinson's disease; anti-Parkinson drug; C-11]raclopride; C-11]GSK-189254; dopamine D-2 receptor; histamine H-3 receptor; dual-action pharmaceutical; pharmacokinetic modeling; REFERENCE TISSUE MODEL; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; H3; RECEPTOR; IN-VIVO; ANTAGONISTS; RELEASE; MODULATION; OCCUPANCY; DISCOVERY;

D O I：

10.1021/acs.molpharmaceut.2c00121

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 (D-2/D-3 agonist/H-3 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 D-2/D-3 receptor ligand [C-11]raclopride or the histamine H-3 receptor ligand [C-11]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [C-11]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 [C-11]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (V-T) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D-2/3 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 V-T values of [C-11]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H-3 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 D-2/D-3 receptors and an antagonist at histamine H-3 receptors could be demonstrated in the rat brain with [C-11]raclopride and [C-11]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D-2/D-3 and moderate (submicromolar) affinity to H-3 receptors.

引用

页码：2287 / 2298

页数：12

共 67 条

[11] HISTAMINE H-3 RECEPTORS MODULATE THE RELEASE OF [H-3] ACETYLCHOLINE FROM SLICES OF RAT ENTORHINAL CORTEX - EVIDENCE FOR THE POSSIBLE EXISTENCE OF H-3 RECEPTOR SUBTYPES [J].