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. 2021 Feb 15:34:127777.
doi: 10.1016/j.bmcl.2021.127777. Epub 2021 Jan 6.

Discovery of carbon-11 labeled sulfonamide derivative: A PET tracer for imaging brain NLRP3 inflammasome

Yulong Xu  1 , Yiming Xu  2 , Hallie Blevins  2 , Yu Lan  1 , Yan Liu  1 , Gengyang Yuan  3 , Robin Striar  1 , Julia S Zagaroli  1 , Darcy R Tocci  1 , Amelia G Langan  1 , Can Zhang  4 , Shijun Zhang  2 , Changning Wang  5
Affiliations

Discovery of carbon-11 labeled sulfonamide derivative: A PET tracer for imaging brain NLRP3 inflammasome

Yulong Xu et al. Bioorg Med Chem Lett. .

Abstract

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [11C]1 exhibited rapid blood-brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [11C]1, thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains.

Keywords: Blockable uptake; Blood-brain barrier (BBB) penetration; NLRP3; Positron emission tomography (PET); Sulfonamide derivative.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Structures of some representative NLRP3 inflammasome inhibitors.
Fig. 2.
Fig. 2.
Design of the NLRP3 PET tracer in our group.
Scheme 1.
Scheme 1.
Synthesis of sulfonamide derivative 1 and [11C]1a
Fig. 3.
Fig. 3.
Biodistribution histogram of [11C]1 in C57BL/6 mice. All data are the mean. Data are expressed as the percentage of injected dose per cubic centimeter (% ID/cc).
Fig. 4.
Fig. 4.
Above: Sagittal PET/CT images of [11C]1 in baseline and blocking experiments (summed 15–60 mins). Below (left): Baseline TACs in six representative mouse brain regions. Below (right): TACs of baseline and blocking experiments in C57BL/6 mouse brains. All data are the mean. Data are expressed as the percentage of injected dose per cubic centimetre (% ID/cc).
See this image and copyright information in PMC

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