Antibody-Based PET Imaging of Misfolded Superoxide Dismutase 1 in an Amyotrophic Lateral Sclerosis Mouse Model.

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.