title: Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical.
abstract: Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor. Rat brain uptake of intravenously injected [125I]WYE-230949 was low (0.11 %ID/g) and the ratio of specific: non-specific binding was less than 1.4, as determined by ex vivo autoradiography. In plasma, metabolism of [125I]WYE-230949 into a less lipophilic species occurred, such that less than 38% of the parent compound remained 30 minutes after injection. Brain uptake and metabolism of [125I]WYE-230949 were increased and specific binding was reduced in anaesthetised compared to conscious rats. [125I]WYE230949 is not a potential radiotracer for imaging rat histamine H3 receptors in vivo due to low brain uptake, in vivo metabolism of the parent compound and low specific binding.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: David Y
authors.initials: DY
authors.lastname: Lewis
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sue
authors.initials: S
authors.lastname: Champion
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Wyper
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Dewar
authors.affiliation: Department of Clinical Physics, Greater Glasgow NHS Trust and University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Pimlott
mesh_terms: D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3; C000600918:WYE-230949; C031000:benzimidazole