The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases

• Published in: Nature communications Vol. 14; no. 1; pp. 6750 - 12
• Main Authors: Smith, Ruben, Capotosti, Francesca, Schain, Martin, Ohlsson, Tomas, Vokali, Efthymia, Molette, Jerome, Touilloux, Tanja, Hliva, Valerie, Dimitrakopoulos, Ioannis K., Puschmann, Andreas, Jögi, Jonas, Svenningsson, Per, Andréasson, Mattias, Sandiego, Christine, Russell, David S., Miranda-Azpiazu, Patricia, Halldin, Christer, Stomrud, Erik, Hall, Sara, Bratteby, Klas, Tampio L’Estrade, Elina, Luthi-Carter, Ruth, Pfeifer, Andrea, Kosco-Vilbois, Marie, Streffer, Johannes, Hansson, Oskar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 14/63; 59/57; 59/78; 692/53/2421; 692/617/375/346/1718; 692/617/375/365; alpha-Synuclein - metabolism; Atrophy; Autoradiography; Basic Medicine; Binding; Cerebellum; Diagnosis; Fluorine isotopes; Health services; Humanities and Social Sciences; Humans; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Movement disorders; multidisciplinary; Multiple System Atrophy - metabolism; Neurodegenerative diseases; Neurosciences; Neurovetenskaper; Parkinson Disease - metabolism; Parkinson's disease; Pathology; Patients; Positron emission; Positron emission tomography; Science; Science (multidisciplinary); Substantia alba; Synuclein; Target detection; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42305-3

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [ 18 F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [ 18 F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [ 18 F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies. A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.