Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical

Lewis, D. Y., Champion, S. , Wyper, D., Dewar, D. and Pimlott, S. (2014) Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical. PLoS ONE, 9(12), e115876. (doi: 10.1371/journal.pone.0115876) (PMID:25542008) (PMCID:PMC4277420)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dewar, Dr Deborah and Pimlott, Dr Sally and Lewis, Dr David and Champion, Dr Sue
• Authors: Lewis, D. Y., Champion, S., Wyper, D., Dewar, D., and Pimlott, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in PLoS ONE 9(12):e115876
• Publisher Policy: Reproduced under a Creative Commons License