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PET imaging of the CNS histamine H3 receptor using [11C]GSK189254A
Poster Presentations / NeuroImage 31 (2006) T44 – T186
T47
Poster Presentation No.: 004
PET imaging of the CNS histamine H3 receptor using [11C]GSK189254A Christophe Plisson,1 D. Bender,2 S. Ashworth,1 E. Rabiner,1 C. Johnson,3 V. Cunningham,1 A. Gee1 1
GlaxoSmithKline, Imaging Centre, UK 2 Aarhus PET Centre, DK 3 GlaxoSmithKline, New Frontiers Science Park, Harlow, UK
Histamine is a neurotransmitter in the central nervous system (CNS) as well as being present peripherally and exerts its action through four distinct histamine receptor subtypes, H1, H2, H3 and H4. The histamine H3 receptor (H3R) has been reported to regulate the synthesis and release of histamine, as well as other neurotransmitters, such as acetylcholine, noradrenaline, dopamine and serotonin. The CNS H3R has been implicated in a number of pathologies, and therefore there is a considerable interest in the pharmacology of this receptor. In order to help characterise H3R status in healthy volunteers and patients, we developed the radiosynthesis of [11C-Nmethyl]-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nic otamide [11C]GSK189254A), a potential PET radioligand for imaging and quantifying the H3R. The in vitro affinity of GSK189254A for the histamine H3R was determined by a competition assay using [3H]-alpha-methylhistamine binding to native H3R expressed in human cerebral cortex tissue. GSK189254A exhibited a high affinity for the human H3R (pKi = 9.59) and a high selectivity over other receptors (e.g. pKi (H1R) <5.5). [11C]GSK189254A was prepared by N-alkylation of the corresponding carboxamide precursor using [11C]methyl iodide. Typical syntheses provide 1.0 to 2.6 GBq of [11C]GSK189254A at the end of synthesis (EOS). For all the productions, the radiochemical purity was greater than 99% and the specific activity ranged from 50 to 500 GBq/Amol at EOS. Initial in vivo evaluation of [11C]GSK189254A was performed in pig. Brain PET images were acquired from 0 to 90 min following i.v. administration of the radiotracer. [11C]GSK189254A readily entered the brain; the radioactivity reached its peak uptake at 25 min after administration of the radiotracer and then steadily declined over the remainder of the study. The regional brain distribution of [11C]GSK189254A reflected the known distribution of the histamine H3R, with a higher accumulation in the striatum and cortical regions. The highest ratios relative to cerebellum, a brain region known to possess very low levels of H3R, occurred at 85 min post-injection and were 4.7, 2.9, 2.7 and 2.0 for the striatum, frontal cortex, parietal cortex and occipital cortex, respectively. [11C]GSK189254A was co-administered with escalating doses of ciproxifan, a selective H3 antagonist (0.06, 0.6 and 2.0 mg/kg). A dose-dependent decrease of [11C]GSK189254A uptake in the H3-rich regions of the brain was observed. At a dose of 2.0 mg/kg, the tissue to cerebellum ratios were 1.22, 1.08, 0.99 and 0.91 for the striatum, frontal cortex, occipital cortex and parietal cortex, respectively, at 85 min post-injection. These findings suggested that [11C]GSK189254A is a very promising radioligand for imaging and quantifying the H3R. This radioligand is being progressed into man, and pilot data from a human PET study will be reported. doi:10.1016/j.neuroimage.2006.04.038
T47
Poster Presentation No.: 004
PET imaging of the CNS histamine H3 receptor using [11C]GSK189254A Christophe Plisson,1 D. Bender,2 S. Ashworth,1 E. Rabiner,1 C. Johnson,3 V. Cunningham,1 A. Gee1 1
GlaxoSmithKline, Imaging Centre, UK 2 Aarhus PET Centre, DK 3 GlaxoSmithKline, New Frontiers Science Park, Harlow, UK
Histamine is a neurotransmitter in the central nervous system (CNS) as well as being present peripherally and exerts its action through four distinct histamine receptor subtypes, H1, H2, H3 and H4. The histamine H3 receptor (H3R) has been reported to regulate the synthesis and release of histamine, as well as other neurotransmitters, such as acetylcholine, noradrenaline, dopamine and serotonin. The CNS H3R has been implicated in a number of pathologies, and therefore there is a considerable interest in the pharmacology of this receptor. In order to help characterise H3R status in healthy volunteers and patients, we developed the radiosynthesis of [11C-Nmethyl]-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nic otamide [11C]GSK189254A), a potential PET radioligand for imaging and quantifying the H3R. The in vitro affinity of GSK189254A for the histamine H3R was determined by a competition assay using [3H]-alpha-methylhistamine binding to native H3R expressed in human cerebral cortex tissue. GSK189254A exhibited a high affinity for the human H3R (pKi = 9.59) and a high selectivity over other receptors (e.g. pKi (H1R) <5.5). [11C]GSK189254A was prepared by N-alkylation of the corresponding carboxamide precursor using [11C]methyl iodide. Typical syntheses provide 1.0 to 2.6 GBq of [11C]GSK189254A at the end of synthesis (EOS). For all the productions, the radiochemical purity was greater than 99% and the specific activity ranged from 50 to 500 GBq/Amol at EOS. Initial in vivo evaluation of [11C]GSK189254A was performed in pig. Brain PET images were acquired from 0 to 90 min following i.v. administration of the radiotracer. [11C]GSK189254A readily entered the brain; the radioactivity reached its peak uptake at 25 min after administration of the radiotracer and then steadily declined over the remainder of the study. The regional brain distribution of [11C]GSK189254A reflected the known distribution of the histamine H3R, with a higher accumulation in the striatum and cortical regions. The highest ratios relative to cerebellum, a brain region known to possess very low levels of H3R, occurred at 85 min post-injection and were 4.7, 2.9, 2.7 and 2.0 for the striatum, frontal cortex, parietal cortex and occipital cortex, respectively. [11C]GSK189254A was co-administered with escalating doses of ciproxifan, a selective H3 antagonist (0.06, 0.6 and 2.0 mg/kg). A dose-dependent decrease of [11C]GSK189254A uptake in the H3-rich regions of the brain was observed. At a dose of 2.0 mg/kg, the tissue to cerebellum ratios were 1.22, 1.08, 0.99 and 0.91 for the striatum, frontal cortex, occipital cortex and parietal cortex, respectively, at 85 min post-injection. These findings suggested that [11C]GSK189254A is a very promising radioligand for imaging and quantifying the H3R. This radioligand is being progressed into man, and pilot data from a human PET study will be reported. doi:10.1016/j.neuroimage.2006.04.038