AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects

Abstract

The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO. Its efficacy has been demonstrated in rodent behavioural models of cognition. In human subjects, AZD5213 was safe and well tolerated following repeated doses (1-14 mg/d) and demonstrated a short (∼5 h) half-life. In this PET study H3RO was measured using the radioligand [11C]GSK189254 ([11C]AZ12807110) in seven young male volunteers following single doses of AZD5213 (0.05-30 mg). H3RO was calculated using the Lassen plot method. The plasma concentrations and the affinity constant (K i,pl 1.14 nmol/l, corresponding to the plasma concentration required to occupy 50% of available receptors) were used to estimate the H3RO time-course. AZD5213 showed dose and concentration dependent H3RO ranging from 16 to 90%. These binding characteristics and the pharmacokinetic profile of AZD5213 indicate that high daytime and low night-time H3RO could be achieved following once daily oral dosing of AZD5213. Fluctuations of H3RO following circadian rhythm of the histamine system may be expected to reduce the risk of sleep disruption while maintaining daytime efficacy. AZD5213 may thus be an optimal compound to evaluate the clinical benefit of selective H3 antagonism in cognitive disorders.

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

“…The clinical development of MK-3134 and MK-0249, however, has been halted for strategic reasons as determined by Merck. Furthermore, PET could be used to select among these compounds and others in development with different pharmacokinetic profiles across indications to optimize therapeutic effects when needed most and potentially minimize unwanted effects such as nighttime alerting (18).…”

“…Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 …”

“…The latter radiotracer can also be used to quantify H3 receptor availability but requires high specific activity (16,17) and has slow uptake kinetics; nevertheless, it was documented to be suitable for H3 RO determinations. Also, 11 C-AZ12807110 was recently used to assess H3 RO using the Lassen plot method (18).…”

Neuronal histamine and cognitive symptoms in Alzheimer's disease

“…Given that episodic memory impairments are among the first cognitive symptoms in Alzheimer's disease (Irish et al, 2011) and given that both HDC and H1R deficient mice show impaired temporal order (Dere et al, 2003) or episodic-like memory performance (Dere et al, 2008) it would be interesting to assess the effects of H3R antagonists on episodic-like memory in transgenic mouse models of Alzheimer's disease. Given that the pro-cognitive effects of thioperamine and other H3R antagonists are well documented in animal research and since there are a number of non-imidazole histamine H3R inverse agonists available that have pro-cognitive properties and are safe for humans (Ashworth et al, 2014(Ashworth et al, , 2010Brioni et al, 2011;Jucaite et al, 2013;Othman et al, 2013;Plisson et al, 2009), a more careful analysis of these candidate drugs in clinical trials with Alzheimer patients and patients with mild cognitive impairment (a prodromal stage of Alzheimer's disease) seems justified.…”

Ergoline‐Derived Inverse Agonists of the Human H3 Receptor for the Treatment of Narcolepsy

“…Since carbonyl amides are a recognition element for Pgp transporter-mediated efflux, their replacement is a frequently used strategy to decrease efflux and enhance brain exposure. [29] As a first step, the amide was replaced with a 1,2,4-oxadiazole ring (20), a classical amide bioisostere. [30] This modification dramatically improved the permeation ratio in the MDCK assay, indicating decreased affinity for the Pgp transporter.…”