P1–447: Pharmacological MRI of H3 receptor antagonist GSK189254 in the rat brain

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Histamine H3 receptors (H3R) mediate the activity of several central neurotransmitter systems involved in alertness, wakefulness and higher cognitive processes. H3R antagonists (H3RA) are sought as potential cognition enhancers, for dementia and sleep disorders. The complexity of these behaviors makes the development of a pharmacodynamic (PD) assay that is translatable to humans particularly valuable. Pharmacological MRI (phMRI) detects blood oxygenation level–dependent (BOLD) responses to compounds that penetrate the brain, in the absence of other stimuli, and therefore could provide a suitable PD readout. GSK189254, a potent and selective H3RA, was investigated using a dosing protocol predicted to achieve ≤90% H3R occupancy in the rat brain in vivo. [H]–GSK189254 was prepared to compare phMRI responses with autoradiographic localization. Experiments complied with GSK ethical and UK legal requirements. Male SD rats (369±41g) were imaged under α–chloralose anesthesia in a Bruker 4.7T/40 scanner using a standard multi–echo GE sequence (TR 1.01s; mean TE 12.5ms, α 30°; voxel 0.5x0.5x0.5mm, 40 slices, 200 scans in 3.9h). Core temperature, blood pressure and respiration, and arterial pCO2, pO2 and pH measured before and after phMRI, remained within normal limits. GSK189254 (1mg/kg/hr, n=12) or saline vehicle (1ml/kg/hr, n=12) were infused iv over 1 hour, between scans 52 and 103. Images were processed using SPM'99 (www.fil.ion.ucl.ac.uk) and MELODIC (www.fmrib.ox.ac.uk) software. Data were scaled to the global brain signal and activation maps were derived representing significant correlations with the pharmacokinetic input function. For autoradiography, [H]–GSK189254 (1 nM) was incubated with rat brain slices (1 hour), then apposed to Hyperfilm (Amersham) (5 weeks); non–specific binding was detected with Imetit (10μM). GSK189254 (but not vehicle) produced striking BOLD increases in prefrontal, cingulate and sensory cortices, striatum, hippocampus and hypothalamus; small decreases appeared confined to cerebral ventricle and sinuses. [H]–GSK189254 autoradiographic distribution correlated well with BOLD increases and with published H3R localization, except in nucleus accumbens and substantia nigra where BOLD responses were not significant. The data suggest phMRI could be a useful PD marker for such compounds, in animals and humans; the brain metabolic effects detected with GSK189254 support the compound's potential utility for cognitive enhancement.

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