Selective PET Tracer for Alpha Synucleinopathies: Novel Diagnosis of Parkinson’s Disease (PD), Lewy Body Dementia (LBD), and Multiple System Atrophy (MSA)

Ziel/Aim Imaging of α-synuclein (α-syn) aggregates is of significant interest for studies of neurodegenerative diseases such as PD, MSA, and LBD. We aim to develop a selective fluorine-18 labeled tracer with favorable pharmacokinetics (PK) for in vivo PET imaging.

Methodik/Methods Some diarylbisthiazole (DABTA) based compounds that show high binding affinity to α-syn over other misfolded protein aggregates were identified. Based on these findings, a small focused library of DABTAs is being designed and synthesized. Some of the lead candidates were radiofluorinated via ruthenium-mediated deoxyfluorination of phenols (1), and then evaluated by in vitro tests for binding and plasma stability assays, log D analysis. Promising candidates were characterized by in-vivo studies of biodistribution and metabolic stability in mice, and will be further characterized by brain autoradiography.

Ergebnisse/Results Based on binding affinity assays of the DABTAs, it has concluded that the presence of a methylenedioxy moiety and suitable chemical moieties contribute significantly to high binding affinity of DABTAs (K _i 3–12 nM) and excellent selectivity (> 100 REFfolds) to α-syn. In vivo, the most promising tracer, the plasma stable BUst-1 with log D 1.97 showed a brain uptake and clearance of 6.15 ± 1.56 and 1.69 ± 0.19 %ID/g at 5 and 60 minutes p.i. respectively, with no radiometabolites in the brain at 60 minutes p.i.

Schlussfolgerungen/Conclusions We identified some DABTAs with high affinity and in-vitro selectivity for α-syn aggregates. By reducing their lipophilicity we were able to develop a tracer, BUst-1 with improved brain uptake and clearance. In vivo studies in α-syn transgenic mice are ongoing.

• Literatur/References

• 1 Tang Pingping, Wang Weike. , and Ritter Tobias. J Am Chem Soc 2011; 133 ( (30) ), 11482-11484 DOI: 10.1021/ja2048072.