Deposition of intracellular -synuclein fibrils is implicated in neurodegenerative parkinsonian disorders, while high-contrast in vivo detection of -synuclein depositions has been unsuccessful in animal models and humans. Here, we have developed a bimodal imaging probe, C05-05, for visualizing -synuclein inclusions in the brains of living animals modeling -synuclein propagation. In vivo optical and PET imaging of a mouse model demonstrated sensitive detection of -synuclein aggregates by C05-05, revealing a dynamic propagation of fibrillogenesis along neural pathways followed by disruptions of these structures. Moreover, longitudinal 18F-C05-05-PET of a marmoset model captured widespread dissemination of fibrillary pathologies accompanied by neurodegeneration detected by dopamine transporter PET. In addition, in vitro assays demonstrated the high-affinity binding of 18F-C05-05 to -synuclein versus other protein pathologies in human brain tissues. Collectively, we propose a new imaging technology enabling etiological and therapeutic assessments of -synuclein pathogenesis at nonclinical levels, highlighting the applicability of C05-05 to clinical PET.
bioRxiv Subject Collection: Neuroscience