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Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2021-10-15 , DOI: 10.1007/s00259-021-05578-8
Daniele Bertoglio 1, 2 , Jeroen Verhaeghe 1 , Alan Miranda 1 , Leonie Wyffels 1, 3 , Sigrid Stroobants 1, 2, 3 , Ladislav Mrzljak 4 , Vinod Khetarpal 4 , Mette Skinbjerg 4 , Longbin Liu 4 , Celia Dominguez 4 , Ignacio Munoz-Sanjuan 4 , Jonathan Bard 4 , Steven Staelens 1, 2
Affiliation  

PURPOSE As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington's disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. METHODS After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography. RESULTS Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography. CONCLUSION With clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

中文翻译:

新型放射性配体 [11C]CHDI-626 用于亨廷顿病突变亨廷顿蛋白聚集体 PET 成像的纵向临床前评估。

目的 由于目前正在研究旨在降低亨廷顿病 (HD) 中突变亨廷顿蛋白 (mHTT) 脑水平的几种疗法,mHTT 的无创正电子发射断层扫描 (PET) 成像可用于直接评估治疗效果和监测疾病进展。在这里,我们在 HD 的 zQ175DN 小鼠模型中对用于 mHTT PET 成像的新型放射性配体 [11C]CHDI-626 进行了表征和纵向评估。方法 在评估放射性代谢物和放射性配体动力学后,我们在野生型 (WT, n = 17) 和杂合子 (HET, n = 23) zQ175DN 的 3、6、9 和 13 个月大 (M) 进行纵向动态 PET 成像老鼠。进行统计分析以评估时间和基因型差异。每个纵向时间点的横断面队列都包括在尸检 [3H]CHDI-626 放射自显影中。结果 尽管新陈代谢和动力学很快,放射性配体仍适用于 mHTT 的 PET 成像。纵向定量可以区分已经处于表现前阶段 (3 M) 的基因型,显示与年龄相关的 HET 小鼠信号增加与 mHTT 总负荷进展平行,这得到了验尸 [3H]CHDI-626 放射自显影的支持。结论 随着临床评估的进行,[11C]CHDI-626 PET 成像似乎是监测 HD 自然进展和评估 mHTT 降低疗法的合适的临床前候选标志物。纵向定量可以区分已经处于表现前阶段 (3 M) 的基因型,显示与年龄相关的 HET 小鼠信号增加与 mHTT 总负荷进展平行,这得到了验尸 [3H]CHDI-626 放射自显影的支持。结论 随着临床评估的进行,[11C]CHDI-626 PET 成像似乎是监测 HD 自然进展和评估 mHTT 降低疗法的合适的临床前候选标志物。纵向定量可以区分已经处于表现前阶段 (3 M) 的基因型,显示与年龄相关的 HET 小鼠信号增加与 mHTT 总负荷进展平行,这得到了验尸 [3H]CHDI-626 放射自显影的支持。结论 随着临床评估的进行,[11C]CHDI-626 PET 成像似乎是监测 HD 自然进展和评估 mHTT 降低疗法的合适的临床前候选标志物。
更新日期:2021-10-15
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