Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
ACS Sens. 2024 May 24;9(5):2605-2613. doi: 10.1021/acssensors.4c00313. Epub 2024 May 8.
Several new lines of research have demonstrated that a significant number of amyloid-β peptides found in Alzheimer's disease (AD) are truncated and undergo post-translational modification by glutaminyl cyclase (QC) at the N-terminal. Notably, QC's products of Abeta-pE3 and Abeta-pE11 have been active targets for investigational drug development. This work describes the design, synthesis, characterization, and in vivo validation of a novel PET radioligand, [F]PB0822, for targeted imaging of QC. We report herein a simplified and robust chemistry for the synthesis of the standard compound, [F]PB0822, and the corresponding [F]PB0822 radioligand. The PET probe was developed with 99.9% radiochemical purity, a molar activity of 965 Ci.mmol, and an IC of 56.3 nM, comparable to those of the parent PQ912 inhibitor (62.5 nM). Noninvasive PET imaging showed that the probe is distributed in the brain 5 min after intravenous injection. Further, in vivo PET imaging with [F]PB0822 revealed that AD 5XFAD mice harbor significantly higher QC activity than WT counterparts. The data also suggested that QC activity is found across different brain regions of the tested animals.
几项新的研究表明，阿尔茨海默病（AD）中发现的大量淀粉样β肽被截断，并在 N 端通过谷氨酰胺环化酶（QC）进行翻译后修饰。值得注意的是，QC 的 Abeta-pE3 和 Abeta-pE11 产物一直是药物研发的目标。本工作描述了一种新型 PET 放射性配体[F]PB0822 的设计、合成、表征和体内验证，用于靶向成像 QC。我们在此报告了一种简化和稳健的合成标准化合物[F]PB0822 和相应的[F]PB0822 放射性配体的化学方法。该 PET 探针具有 99.9%的放射性化学纯度、965 Ci.mmol 的摩尔活性和 56.3 nM 的 IC，与母体 PQ912 抑制剂（62.5 nM）相当。非侵入性 PET 成像显示，探针在静脉注射后 5 分钟内分布在大脑中。此外，[F]PB0822 的体内 PET 成像显示，5XFAD AD 小鼠比 WT 对照具有显著更高的 QC 活性。该数据还表明，QC 活性存在于测试动物的不同大脑区域。
