Synthesis and preliminary biological evaluation of a novel PET tracer for α-synuclein PET imaging

BackgroundAccumulation of α-synuclein is a major hallmark of Parkinson's disease (PD). The development of PET tracers to visualize aggregated α-synuclein is useful for early diagnosis and treatment of PD.PurposeThis study aims to design and synthetize a novel PET tracer, i.e., 18F-YM, for for alpha-synuclein PET imaging, and conduct preliminary biological evaluation.MethodsFirstly, based on benzothiazole scaffolds, 2-((3-fluorobenzyl)thio)-6-(3-[fluorine-18] propoxy)benzo[d]thiazole, a small molecule compound, denoted as 18F-YM, was prepared as PET tracer and labeled using Cu(II) mediated radiofluorination methods. The imaging properties of the tracer were primarily evaluated through PET imaging at A53T mice and normal mice. Additionally, the imaging properties of the tracer were also investigated through biodistribution experiments as well as ex vivo autoradiography and pathological analysis. Then, through chemical synthesis, compounds Sn-YM and 19F-YM were obtained, and the Sn-YM was labeled with 18F using organic tin fluoride method whilst the resulting product 18F-YM was verified by high performance liquid chromatography. The in vitro stability and octanol-water partition coefficient of 18F-YM were determined. Finally, small animal Micro PET imaging was employed to assess the affinity of 18F-YM for α-synuclein, and autoradiography, pathological analysis, and biodistribution were used to validate the results of small animal Micro PET imaging.ResultsObserved results show that 18F labeled small molecule compound is prepared in nearly 1 h with an undecayed yield greater than 10% and a radiochemical purity greater than 95%. In vivo PET imaging of 18F-YM reveals that more radioactivity is significantly detected in the brains of A53T mice than those of normal mice after administration of 18F-YM. Quantitative analysis shows that the uptake values in the brain of A53T mice and normal mice are (2.35±0.06) %ID/g and (1.38±0.15) %ID/g, respectively while ex vivo autoradiography and histological examination confirm the possibility of detection of aggregated α-synuclein in thalamus, substantia nigra and striatum using 18F-YM. Furthermore, a biodistribution study in normal mice reveals that 18F-YM can be quickly cleaned from the brain of normal mice, indicating that the non-specific binding of 18F-YM in the brain is low, which allowed for obtaining good contrast images.ConclusionThis preclinical study demonstrates that the benzothiazole analog, 18F-YM, owns preferable imaging prosperities, hence be a new candidate for α-synuclein PET imaging.