Measuring H3 receptor occupancy of the experimental anti-Parkinsonian drug AG0029, using [11C]GSK-189254 and PET

Nafiseh Ghazanfari, Aren van Waarde, Jurgen Sijbesma, Janine Doorduin, David Vállez García, Maria Kominia, Martin Koelewijn, Khaled Attia, Ton J Visser, André Heeres, Antoon Willemsen, Erik F. de Vries, Rudi Dierckx, Philip H. Elsinga

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Aim/Introduction: Inadequacies of currently designed drugs in treating neurodegenerative disorders have promoted efforts to develop novel drugs interacting with multiple targets. As part of a collaborative drug discovery program, AG-0029 was developed. This compound has agonist affinity to dopamine (0.08 nM) and antagonist affinity (111 nM) to histamine H3 receptors and may enhance both the motor and cognitive symptoms of Parkinson’s disease. Previously, we reported on the occupancy of dopamine D2/D3 receptors in the rodent brain by AG0029 [1]. In the present study, we aimed to quantitatively assess the engagement of AG-0029 with cerebral histamine H3 receptors, using PET. Materials and Methods: Two dynamic PET scans of 60 min with arterial blood sampling were made in 12 healthy male Wistar rats (body weight 373±32 g), at a one-week interval, using 49±8 MBq of the histamine H3 receptor ligand [11C]GSK-189254. The animals were first scanned at baseline and subsequently after administration of either 1 or 10 mg/kg of AG-0029 in saline (i.v., 5 min before tracer injection, n=6 for each drug dose). Results: In baseline scans, the regional distribution of the tracer corresponded to the known distribution of histamine H3 receptors in the rodent brain. Considerable uptake was noticed in frontal-cortex and olfactory-bulb, and low uptake in occipital-cortex and cerebellum. A region-of-interest was manually drawn around the frontal areas with high uptake and a standard elliptical ROI was placed in the cerebellum. Tracer uptake in the cerebellum was not significantly affected by drug pretreatment, in contrast to uptake in the frontal target regions. Frontal-to-cerebellum ratios of radioactivity minus one were plotted as a function of time. The maximum of this curve is an estimation of tracer binding potential (BP). BP values were not reduced after pretreatment with 1 mg/kg AG-0029 (from 2.03±0.24 to 1.97±0.20) but were significantly reduced by 10 mg/kg of the test drug (to 1.33±0.22). Calculated H3 receptor occupancies were 3±10 and 34±11%, respectively. The tracer was slowly metabolized and tracer metabolism was not significantly affected by drug pretreatment. At 62±9 min after injection, 50% of the plasma radioactivity still represented parent compound. Preliminary data analysis using a simplified reference tissue model fit showed the same trends as the ratio method. Conclusion: Our PET data indicated negligible histamine H3 receptor occupancy after administration of 1 mg/kg, but considerable (34%) occupancy after administration of 10 mg/kg AG-0029.
References: A. van Waarde, EJNMM, vol. 47, no. Suppl. 1, p. S114, 2020.
Original languageEnglish
Article numberOP-0278
Pages (from-to)S108-S109
Number of pages2
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue numberSuppl.1
Publication statusPublished - Oct-2021


  • GSK189254

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