Rousseau Jacques A, Maier Marcel, Ait-Mohand Samia, Dumulon-Perreault Véronique, Sarrhini Otman, Tremblay Sébastien, Rousseau Etienne, Salzmann Michael, Guérin Brigitte
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
AL-S Pharma AG, Schlieren, Zurich, Switzerland; and.
J Nucl Med. 2025 Jan 3;66(1):130-135. doi: 10.2967/jnumed.124.268343.
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Imaging with [Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice ( = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [Zr]Zr-DFO-α-miSOD1 is comparable to that for other Zr-based tracers currently used in humans. This work thus establishes that [Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring.
肌萎缩侧索硬化症（ALS）是一种罕见的神经退行性疾病，其特征是运动皮层、脑干和脊髓中的运动神经元丧失。超氧化物歧化酶1（SOD1）基因突变导致其蛋白质产物错误折叠，是ALS的常见病因。目前，尚无获批的ALS诊断工具。在此，我们展示了一种PET放射性示踪剂[Zr]Zr-去铁胺（DFO）-α-miSOD1的研发过程，该示踪剂可选择性靶向错误折叠的SOD1（misSOD1）。DFO-α-miSOD1通过将α-miSOD1抗体与DFO偶联并标记Zr制备而成。进行了一项纵向成像研究，以确定在给予[Zr]Zr-DFO-α-miSOD1后，用于检测过表达misSOD1的转基因小鼠和野生型小鼠中misSOD1聚集的最佳小鼠年龄和时间。部分小鼠要么与过量的α-miSOD1共同注射，要么用去糖基化的[Zr]Zr-DFO-α-miSOD1成像，以评估靶点特异性。通过外推小鼠生物分布实验数据估算了[Zr]Zr-DFO-α-miSOD1的体内辐射剂量。在给药后第10天，用[Zr]Zr-DFO-α-miSOD1成像在136日龄的转基因小鼠中效果最佳。与野生型小鼠相比，在ALS转基因小鼠的脊髓和软骨中检测到[Zr]Zr-DFO-α-miSOD1有显著蓄积（P = 0.01）。放射性示踪剂的蓄积具有选择性，且可被过量的α-miSOD1阻断。去糖基化的[Zr]Zr-DFO-α-miSOD1可实现对misSOD1的高对比度检测，但易于聚集。[Zr]Zr-DFO-α-miSOD1的剂量学与目前用于人体的其他基于Zr的示踪剂相当。因此，这项工作证实了[Zr]Zr-DFO-α-miSOD1 PET可在转基因小鼠中检测到misSOD1，为其在ALS早期诊断和治疗监测中的应用铺平了道路。
