2. Academic Validation
  3. Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers

Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers

  • Eur J Med Chem. 2020 Oct 15;204:112623. doi: 10.1016/j.ejmech.2020.112623.
Marius Ozenil 1,  Katharina Pacher 1,  Theresa Balber 2,  Chrysoula Vraka 1,  Alexander Roller 3,  Wolfgang Holzer 4,  Helmut Spreitzer 4,  Markus Mitterhauser 2,  Wolfgang Wadsak 5,  Marcus Hacker 1,  Verena Pichler 6
Affiliations

Affiliations

  • 1 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
  • 2 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria; Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria.
  • 3 X-ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, Austria.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Austria.
  • 5 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria; CBmed GmbH - Center for Biomarker Research in Medicine, Graz, Austria.
  • 6 Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria. Electronic address: [email protected].
PMID: 32717485 DOI: 10.1016/j.ejmech.2020.112623
Abstract

Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline. Fifteen novel arecoline derivatives were synthesized, characterized and tested for their affinity to the mAChRs M1-M5 and the conceivable off-target acetylcholinesterase. Five arecoline derivatives and arecoline were labeled with carbon-11 in good yields. Arecaidine diphenylmethyl ester (3b), arecaidine bis(4-fluorophenyl)methyl ester (3c) and arecaidine (4-bromophenyl)(4-fluorophenyl)methyl ester (3e) showed a tremendous gain in mAChR affinity compared to arecoline and a pronounced subtype selectivity for M1. Metabolic stability and serum protein binding of [11C]3b and [11C]3c were in line with properties of established brain tracers. Nonspecific binding of [11C]3c was prevalent in kinetic and endpoint experiment on living cells as well as in autoradiography on native mouse brain sections, which motivates us to decrease the lipophilicity of this substance class prior to in vivo experiments.

Keywords

Carbon-11; Muscarinic acetylcholine receptors; Neuroimaging; PET.

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