Fluorescence and Autoradiographic Evaluation of Tau PET Ligand PBB3 to α-Synuclein Pathology

Background: The tau PET ligand 2-((1E, 3E)-4-(6-([C-11] methylamino) pyridin-3-yl) buta-1,3-dienyl) benzo[d] thiazol-6-ol ([C-11] PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non-tau inclusions remains unknown. To clarify whether [C-11] PBB3 binds to alpha-synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from alpha-synucleinopathies patients. Method: Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of alpha-synuclein severity based on the quantitative analysis of alpha-synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for alpha-synuclein and phospho-tau, Prussian blue staining, and in vitro autoradiography with [C-11] PBB3 were performed for these selected samples. Results: PBB3 fluorescence labeled various alpha-synuclein lesions including Lewy bodies, Lewy neurites,spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [C-11] PBB3 at 10nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [C-11] PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region. Conclusions: Given that the maximum concentration of [C-11] PBB3 in human PET scans is approximately 10 nM, the present data imply that alpha-synuclein pathology in Lewy body disease is undetectable by [C-11] PBB3-PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. (C) 2017 International Parkinson and Movement Disorder Society