Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand

Area of Science:

• Neuroscience
• Radiochemistry
• Molecular Imaging

Background:

• Aggregated alpha-synuclein (α-syn) is a key marker in Parkinson's disease (PD) and related synucleinopathies.
• Developing selective positron emission tomography (PET) radioligands for α-syn is crucial for diagnosing and monitoring PD.

Purpose of the Study:

• To characterize KAC-50.1 in vitro and evaluate its in vivo performance as a potential PET radioligand targeting α-syn fibrils.
• To assess the selectivity and binding properties of KAC-50.1 in preclinical models and non-human primates.

Main Methods:

• In vitro characterization of [3H]KAC-50.1 binding to recombinant α-syn fibrils.
• Biochemical studies and post-mortem brain imaging techniques.
• PET imaging in cynomolgus monkeys using [11C]KAC-50.1.

Main Results:

• [3H]KAC-50.1 bound to α-syn fibrils with a KD of 35 nM but demonstrated cross-reactivity with amyloid-beta and tau pathologies.
• [11C]KAC-50.1 showed rapid brain uptake and variable washout kinetics in non-human primates, with retention in white matter.
• Limited selectivity and off-target binding were observed, impacting its utility as a specific α-syn PET tracer.

Conclusions:

• KAC-50.1 exhibits binding to fibrillar α-syn but lacks the required selectivity for use as a PET imaging agent in synucleinopathies.
• The observed cross-reactivity with other protein aggregates and white matter retention in vivo preclude its further development for PD imaging.