Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
Bioorg Med Chem Lett. 2020 Jun 15;30(12):127186. doi: 10.1016/j.bmcl.2020.127186. Epub 2020 Apr 11.
The diaryl sulfonylurea MCC950/CRID3 is a potent NLRP3 inhibitor (IC = 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 [C-urea]MCC950 via carrier added [C]CO fixation chemistry (activity yield = 237 MBq; radiochemical purity >99%; molar activity = 7 GBq/µmol; radiochemical yield (decay-corrected from [C]CO) = 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 [C]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.
二芳基磺酰脲 MCC950/CRID3 是一种强效的 NLRP3 抑制剂（IC = 8 nM），在动物模型中，MCC950 可预防多种与 NLRP3 相关的神经退行性疾病。为了评估 MCC950 的脑摄取并研究其靶标结合情况，我们通过载体添加 [C]CO 固定化学合成了 [C-urea]MCC950（活性产率为 237 MBq；放射化学纯度 >99%；摩尔活性为 7 GBq/µmol；放射性化学产率（从 [C]CO 校正衰变）为 1.1%；从结束照射到合成结束的时间为 31 分钟；在 >1 h 内保持放射化学稳定）。尽管在神经退行性疾病研究中具有临床前疗效，但在小鼠、大鼠和恒河猴中的临床前正电子发射断层扫描（PET）成像研究显示，低摩尔活性 [C]MCC950 的脑摄取量低且清除速度快。基于计算机的预测工具表明 MCC950 在微剂量下具有外排转运体的缺陷，在开发下一代 NLRP3 抑制剂和/或 PET 放射性示踪剂时应考虑这一信息。
