Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor

Authors

  • Linjing Mu,

    1. Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, University Hospital Zürich, Zürich, Switzerland
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  • Daniel Bieri,

    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
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  • Roger Slavik,

    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
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  • Konstantin Drandarov,

    1. Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, University Hospital Zürich, Zürich, Switzerland
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  • Adrienne Müller,

    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
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  • Stjepko Čermak,

    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
    Current affiliation:
    1. Laboratory of Molecular, Neuropharmacology, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
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  • Markus Weber,

    1. Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland
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  • Roger Schibli,

    1. Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, University Hospital Zürich, Zürich, Switzerland
    2. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
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  • Stefanie D. Krämer,

    Corresponding author
    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
    • Department of Nuclear Medicine, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, University Hospital Zürich, Zürich, Switzerland
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  • Simon M. Ametamey

    1. Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH-PSI-USZ, Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland
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Address correspondence and reprint requests to Dr. Stefanie D. Krämer, Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. E-mail: stefanie.kraemer@pharma.ethz.ch

Abstract

The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative (designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochemical purity. Moderate blood–brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was observed in dynamic positron emission tomography (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS) patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2.

image

The cannabinoid type 2 receptor (CB2) plays an important role in neuroinflammatory and neuro–degenerative diseases. [11C]KD2, a new CB2 radioligand, exhibits selectivity towards CB2 receptor in vitro and in vivo in rat. A pilot autoradiography study with spinal cord slices from amyotrophic lateral sclerosis patients with [11C]KD2 suggested the presence of CB2 under disease conditions (Figure). Selective CB2 agonist, GW405833.

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