Session Time: 1:15pm-2:45pm
Location: Les Muses Terrace, Level 3
Objective: The aim is to develop small molecular weight compounds which bind selectively and with high affinity to alpha-synuclein (a-syn) aggregates as diagnostic PET imaging tracers for Parkinson’s disease (PD).
Background: The progressive accumulation of aggregated a-syn in form of Lewy bodies and neurites is the pathognomonic hallmark of PD. The link between a-syn inclusions and disease severity warrants the development of PET tracers as tools to study the distribution and longitudinal changes of the aggregated protein in the human living brain. Due to the low density of a-syn pathology and the high frequency of co-pathologies in PD (e.g. β-amyloid, tau), an a-syn PET tracer must display high binding affinity to a-syn aggregates, high selectivity over other proteinaceous deposits and minimal non-specific binding.
Method: Screening of AC Immune`s proprietary Morphomer™ library of small molecules led to the identification of several hit series. Affinity to aggregated a-syn and selectivity over other proteinopathies were measured in post-mortem PD and Alzheimer’s disease (AD) samples. Several compounds were 18F radiolabeled, and assessed for brain penetration and pharmacokinetic (PK) profile in rodents and non-human primates (NHP).
Results: Following Medicinal Chemistry optimization, a-syn PET tracer candidates were obtained with suitable in vitro and in vivo profiles. These candidates showed single-digit nanomolar affinities binding to Lewy bodies and Lewy neurites (e.g. by high-resolution autoradiography of PD brain sections). In addition, these compounds were selective for a-syn aggregates over β-amyloid and tau aggregates. Pharmacokinetic studies with fluorine-18 labeled candidates demonstrated favorable uptake and washout kinetics in NHP brains.
Conclusion: We optimized hit compounds leading to candidates with high affinity to pathological a-syn aggregates and selectivity over the most commonly observed co-pathologies. The current lead candidate shows an optimized CNS-PET profile with minimal non-specific binding in NHP. Further in vitro and in vivo characterization is ongoing.
To cite this abstract in AMA style:E. Tsika, E. Vokali, J. Molette, M. Ravache, P. Rodriguez, V. Darmency, K. Piorkowska, S. Poli, H. Kroth, F. Capotosti, D. Lowe, J. Stoehr, M. Kosco-Vilbois, A. Pfeifer, A. Muhs. Identification and Characterization of Selective and High Affinity Small Molecules as Positron Emission Tomography (PET) Imaging Tracers for Pathological Alpha-Synuclein [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/identification-and-characterization-of-selective-and-high-affinity-small-molecules-as-positron-emission-tomography-pet-imaging-tracers-for-pathological-alpha-synuclein/. Accessed December 5, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-and-characterization-of-selective-and-high-affinity-small-molecules-as-positron-emission-tomography-pet-imaging-tracers-for-pathological-alpha-synuclein/