Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [11C]MCC950 in healthy animals

James R Hill; Xia Shao; Nicholas L Massey; Jenelle Stauff; Phillip S Sherman; Avril A B Robertson; Peter J H Scott

doi:10.1016/j.bmcl.2020.127186

Synthesis and evaluation of NLRP3-inhibitory sulfonylurea [¹¹C]MCC950 in healthy animals

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127186. doi: 10.1016/j.bmcl.2020.127186. Epub 2020 Apr 11.

Authors

James R Hill¹, Xia Shao², Nicholas L Massey³, Jenelle Stauff², Phillip S Sherman², Avril A B Robertson⁴, Peter J H Scott⁵

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
⁴ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: a.robertson3@uq.edu.au.
⁵ Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: pjhscott@umich.edu.

PMID: 32312583
DOI: 10.1016/j.bmcl.2020.127186

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.

Keywords: Carbon-11 radiochemistry; Molecular imaging; Nod‐like receptor protein 3; Positron emission tomography; Sulfonylurea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon Radioisotopes
Dose-Response Relationship, Drug
Furans
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Indenes
Macaca mulatta
Mice
Mice, Inbred C57BL
Molecular Structure
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides
Sulfones / chemical synthesis
Sulfones / chemistry
Sulfones / pharmacology*

Substances

Carbon Radioisotopes
Furans
Heterocyclic Compounds, 4 or More Rings
Indenes
NLR Family, Pyrin Domain-Containing 3 Protein
Sulfonamides
Sulfones
N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide