Radiotracer development for alpha-synuclein aggregates in neurodegenerative diseases

The aggregation and deposition of alpha-synuclein (aSyn) is the hallmark of a number of neurodegenerative diseases, including Parkinson’s disease (PD) and Multiple System Atrophy (MSA). The development of imaging probes for non-invasive sensitive and specific clinical detection of aggregated aSyn by positron emission tomography (PET) has received enormous attention in the radiopharmacy field as they would facilitate both the precise diagnosis of synucleinopathies and the development of novel therapies. Several development programs have been initiated worldwide on the basis of different lead structures. The low amount of pathology in the patients’s brain necessitates a high affinity of such radiotracers, paired with excellent selectivity over the potential co-pathologies constituted by Aß or tau deposits. We have explored two scaffolds based on a benzothiazole library and on the therapeutic aSyn aggregation inhibitor emrusolmin that is currently in clinical phase II studies. Candidates of both structure families bind to aSyn aggregates with excellent affinity and selectivity in vitro. We radiolabeled the most promising molecules with the positron-emitters 18F (T1/2=110 min) and 11C (T1/2=20 min), respectively, for assessment of in vivo pharmacokinetics in rodents and for subsequent imaging of aSyn in animal models. After thorough evaluation and tolerability studies, one radiotracer was radiolabeled under Good Manufacturing Practice and applied to a patient with MSA in the AMG §13.2b setting. The imaging results revealed specific uptakes in putatively affected brain areas, in line with anticipated binding to aSyn. The currently initiated clinical studies in healthy subjects as well as PD and MSA patients will shed light on the feasibility of PET imaging of synucleinopathies and will be an important pillar for the clinical evaluation of therapeutic agents modulating aSyn deposition.