Introduction: Misfolded tau aggregates associated with clinical syndromes and various neurodegenerative diseases. To date, many second-generation of tau PET tracers were developed to overcome the limitation of the first-generation such as off-target binding. Recently, we developed [¹⁸F]SNFT-1 from compound optimization of [¹⁸F]THK-5351, which showed high affinity for monoamine oxidase-B (MAO-B) as off-target binding. The aim of study was to compare the binding properties of [¹⁸F]SNFT-1 and second-generation tau PET radiotracers to human brain tissues.
Methods: In vitro competitive binding assay were performed for tau aggregates, amyloid aggregates, and recombinant MAO-A and MAO-B. After preparing ¹⁸F-labeled compounds, in vitro autoradiography was performed using frozen human brain sections with immunostaining of phosphorylated tau (tau IHC) for evaluation of binding selectivity.
Results and Discussion: Although second-generation of tau PET radiotracers showed a similar binding affinity for tau aggregates, the off-target binding affinity was different. SNFT-1 showed a high binding affinity for tau aggregates, which was comparable to MK-6240, with no interaction of amyloid aggregates as well as MAO enzymes. In vitro autoradiography demonstrated that distribution of radiotracer‘s binding was similar to tau IHC in the medial temporal area of Alzheimer‘s disease. On the other hands, second-generation tau PET radiotracers showed little binding to the frontal cortex in a case of progressive supranuclear palsy that contains high density tau aggregates.
Conclusion: [¹⁸F]SNFT-1 would be a promising candidates for imaging tau aggregates. Further binding characterization is required to validate the binding of non-AD tau aggregates.