A Structure-Activity Relationship Study of Alpha Synuclein PET Radiotracer M503-1619

Area of Science:

• Neuroscience
• Radiochemistry
• Pharmacology

Background:

• Alpha synuclein (aSyn) aggregation is implicated in synucleinopathies.
• Positron emission tomography (PET) requires specific radiotracers for in vivo imaging.
• [¹¹C]M503-1619 was a previously identified lead compound for aSyn PET development.

Purpose of the Study:

• To conduct a structure-activity relationship (SAR) study on M503-1619.
• To enhance in vitro binding affinity for alpha synuclein (aSyn).
• To identify potential fluorine-18 labeled radiotracers for PET imaging.

Main Methods:

• Structure-activity relationship (SAR) analysis of M503-1619 analogs.
• Radiolabeling with fluorine-18.
• In vitro autoradiography on human postmortem brain sections.
• In vivo PET imaging in non-human primates.

Main Results:

• Strict SARs were identified for fluorine introduction in N-aryl piperazine and benzamide moieties.
• The 2-fluoroethyl analog of M503-1619 showed improved properties.
• The ¹⁸F-labeled tracer demonstrated higher binding in synucleinopathies vs. control tissues.
• The radiotracer exhibited suitable brain uptake and washout kinetics for PET imaging.

Conclusions:

• The developed ¹⁸F-labeled radiotracer showed potential for imaging aSyn in synucleinopathies.
• Formation of brain penetrant radiolabeled metabolites limited further evaluation.
• SAR insights are crucial for designing next-generation aSyn PET ligands that avoid metabolite issues.