Development of acetophenone ligands as potential neuroimaging agents for cholinesterases

Courtney T. Jollymore-Hughes, Ian R. Pottie, Earl Martin, Terrone L. Rosenberry, Sultan Darvesh

Research output: Contribution to journalArticle

Abstract

Association of cholinesterase with β-amyloid plaques and tau neurofibrillary tangles in Alzheimer's disease offers an opportunity to detect disease pathology during life. Achieving this requires development of radiolabelled cholinesterase ligands with high enzyme affinity. Various fluorinated acetophenone derivatives bind to acetylcholinesterase with high affinity, including 2,2,2-trifluoro-1-(3-dimethylaminophenyl)ethanone (1) and 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (2). Such compounds also offer potential for incorporation of radioactive fluorine (18F) for Positron Emission Tomography (PET) imaging of cholinesterases in association with Alzheimer's disease pathology in the living brain. Here we describe the synthesis of two meta-substituted chlorodifluoroacetophenones using a Weinreb amide strategy and their rapid conversion to the corresponding trifluoro derivatives through nucleophilic substitution by fluoride ion, in a reaction amenable to incorporating 18F for PET imaging. In vitro kinetic analysis indicates tight binding of the trifluoro derivatives to cholinesterases. Compound 1 has a Ki value of 7 nM for acetylcholinesterase and 1300 nM for butyrylcholinesterase while for compound 2 these values are 0.4 nM and 26 nM, respectively. Tight binding of these compounds to cholinesterase encourages their development for PET imaging detection of cholinesterase associated with Alzheimer's disease pathology.

Original languageEnglish (US)
Pages (from-to)5270-5279
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
StatePublished - Nov 1 2016

Keywords

  • Acetylcholinesterase
  • Alzheimer's disease
  • Butyrylcholinesterase
  • Cholinesterases
  • Positron Imaging Tomography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Jollymore-Hughes, C. T., Pottie, I. R., Martin, E., Rosenberry, T. L., & Darvesh, S. (2016). Development of acetophenone ligands as potential neuroimaging agents for cholinesterases. Bioorganic and Medicinal Chemistry, 24(21), 5270-5279. https://doi.org/10.1016/j.bmc.2016.08.048