Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [11C]MCC950 in healthy animals |
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| Institution: | 1. Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximillian University, Munich, Germany;2. Munich Cluster for Systems Neurology (SyNergy), Germany;3. Albert-Ludwigs-University, Freiburg, Germany;4. Institute of Neuropathology, Albert-Ludwigs-University, Freiburg, Germany;5. Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University, Munich, Germany;1. Department of Pharmacology and Therapeutics, Watts Building, Trinity College Dublin, Dublin 2, Ireland;2. Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland;3. Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, QC H3G1Y6, Canada;4. Department of Anatomy and Cell Biology, McGill University, Montreal H3G1Y6, Canada;5. Department of Neurology and Neurosurgery, McGill University, Montreal H3G1Y6, Canada |
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| Abstract: | The diaryl sulfonylurea MCC950/CRID3 is a potent NLRP3 inhibitor (IC50 = 8 nM) and, in animal models, MCC950 protects against numerous NLRP3-related neurodegenerative disorders. To evaluate the brain uptake and investigate target engagement of MCC950, we synthesised 11C-urea]MCC950 via carrier added 11C]CO2 fixation chemistry (activity yield = 237 MBq; radiochemical purity >99%; molar activity = 7 GBq/µmol; radiochemical yield (decay-corrected from 11C]CO2) = 1.1%; synthesis time from end-of-bombardment = 31 min; radiochemically stable for >1 h). Despite preclinical efficacy in neurodegeneration studies, preclinical positron emission tomography (PET) imaging studies in mouse, rat and rhesus monkey revealed poor brain uptake of low molar activity 11C]MCC950 and rapid washout. In silico prediction tools suggest efflux transporter liabilities for MCC950 at microdoses, and this information should be taken into account when developing next generation NLRP3 inhibitors and/or PET radiotracers. |
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| Keywords: | Nod‐like receptor protein 3 Positron emission tomography Carbon-11 radiochemistry Molecular imaging Sulfonylurea |
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