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α-Synuclein aggregates abnormally into intracellular inclusions in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and many other neurological disorders, closely connecting with their pathogenesis. The accurate tracking of α-synuclein by targeting probes is of great significance for early diagnosis, disease monitoring, and drug development. However, there have been no promising α-synuclein targeting probes for clinical application reported so far. This overview focuses on various potential α-synuclein targeting probes reported in the past two decades, including small-molecule fluorescent probes and radiolabeled probes. We provide the current status of the development of the small molecular α-synuclein imaging probes, including properties of promising imaging molecules, strategies of processing new probes, limited progress, and growth prospects in this field, expecting to help in the further development of α-synuclein targeting probes.

The highly rigid and planar scaffold with π-conjugated systems has been widely considered to be indispensable for Aβ binding probes. However, the flexible benzyloxybenzene derivative [(125)I]BOB-4 represents an excellent lead candidate for targeting Aβ in AD brains. Based on that, we designed two pairs of more flexible and optically pure diphenoxy derivatives with a chiral center as novel Aβ probes. These compounds possessed high affinity (Ki = 15.8-45.0 nM) for Aβ1-42 aggregates, and (R)-enantiomers showed slightly better binding ability than (S)-enantiomers. In addition, the competition binding assay implied that the optically pure diphenoxy derivatives with more flexible geometry shared the same binding site as IMPY, a classical rigid and planar Aβ probe. For (125)I-radiolabeled enantiomers, (S)-[(125)I]5 and (R)-[(125)I]5, specific plaque labeling on brain sections of Tg mice and AD patients were observed in in vitro autoradiography, persuasively proving the excellent affinity of the probes. In biodistribution, (S)-[(125)I]5 and (R)-[(125)I]5 with relatively low lipophilicity exhibited moderate initial brain uptake (4.37% and 3.72% ID/g at 2 min, respectively) and extremely fast washout from normal mice brain (brain2min/brain60min = 19.0 and 17.7, respectively). In summary, the separate enantiomers displayed similar properties in vitro and in vivo, and (S/R)-[(123)I]5 may be potential SPECT probes for recognizing Aβ plaques in AD brains.