PET/CT of α-Synucleinopathies in Parkinson's Disease Mouse Model with F-18-FS9, a Novel Selective Radiotracer for α-Synuclein Fibrils

Ziel/Aim: A specific F-18-labeled α-synuclein fibrils (α-syn) tracer is an unmet medical need to early diagnose α-synucleinopathies. We have identified compounds based on 4,4´-diarylbisthiazole (DABTA) with high binding affinity to α-syn, excellent selectivity versus tau and Aβ aggregates as well as promising brain uptake kinetics.

Methodik/Methods: F-18-FS9, as the best DABTA from>50 compounds was selected, radiolabeled and purified by RP-HPLC then used for PET/CT of 12 weeks post intrastriatal injection human α-syn (PFF) and monomeric α-synuclein injected (ctrl) mice. The mice underwent 90 min dynamic PET/CT, and the brain regions were segmented based on the Ma-Benveniste-Mirrione mouse template to evaluate uptake values, time activity curves, distribution volume and binding potential. The striatum, cerebellum, olfactory bulb, and left ventricle were considered as regions of interest, reference, and arterial input function, respectively. Additionally, plasma stability, biodistribution, in vivo metabolite analyses, and postmortem autoradiography have been studied.

Ergebnisse/Results: F-18-FS9 shows high binding affinity (Ki 2nM), excellent selectivity to α-syn and favorable pharmacokinetics. It is radiolabeled (yield 25±5% and purity≥99.5%). Autoradiography results of F-18-FS9 show high binding to postmortem PD, DLB and MSA brains, confirmed by IHC. Besides, it shows brain uptake≥7%ID/g (5 min pi) and exceptional stability in brain (t1/2>8h). It shows excellent PET results in PFF vs ctrl with initial uptake > 12%ID/g and fast washout down to 2%ID/g (90 min). The kinetic modeling study represented significantly higher DVR (up to 1.7), on regions close to left striatum of PFF brain versus no specific signal (down to 0.8 ml/cm3, 70-90 min) in control mice brain. The PET/CT results were confirmed by abundant α-synucleinopathies in IHC of mice brains.

Schlussfolgerungen/Conclusions: The combined preclinical and voxel-based analysis encourage us to move on with F-18-FS9 longitudinal PET of the mice towards NHP and 1st-in-Human.

Publikationsverlauf

Artikel online veröffentlicht:
25. März 2024