α-Synuclein (α-syn) is an intrinsically disordered protein that accumulates and aggregates in Lewy bodies and Lewy neurites in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies [1]. Abnormal α-syn aggregation is thought to mirror clinical symptoms and is closely linked to major pathogenic process and early onset by impairing many subcellular functions [[2], [3], [4]]. Native α-syn is a soluble 140-amino-acid protein comprising amphipathic N-terminal region, acidic C-terminal region, and non-amyloid component (NAC) region responsible for α-syn aggregation [4]; NAC region of monomeric α-syn mediates conformational changes of random coil into misfolded cross β-sheet structure, and α-syn has a propensity to form oligomers, protofibrils, and ultimately aggregate into insoluble fibrils [5,6].

α-Syn imaging is a promising approach that enables noninvasive and real-time detection when a suitable tracer exists, yet rational design of α-syn ligands has been hindered due to limited availability of defined crystal structure of α-syn as well as poorly underlying binding mechanism [7]. To date, ligand-based strategy has remained the primary option for α-syn tracer development. According to the established strategies for amyloid tracer development over the past decade, initial attempts were based on structural modification of thioflavin T (staining dye for β-sheet conformation), followed by other scaffolds including N-arylaminonaphthalene sulfonate (bis-ANS), carbocyanine, benzofuranone, phenothiazine, indolinone and indolinone-diene, chalcone, benzimidazole, benzoxazole, 3,5-diphenylpyrazole, N,N-dibenzylcinnamamide, isoxazole, quinoline and bisquinoline (Fig. 1) [[7], [8], [9]]. More recently, radiotracers [18F]SPAL-T-06 [10,11], [18F]ACI-12589 [12], and [18F]F0502B [13] were screened out from respective compound libraries as brain-permeable molecules with high affinity for α-syn aggregates, and were reported to exhibit distinct uptakes in human α-syn pathology regions using positron emission tomography (PET) [[10], [11], [12], [13]]. Nevertheless, the answer to rational design remains elusive due to the small number of promising ligands, and the development of more α-syn tracers is still of great importance.

Our previous studies on developing compact luminol and benzothiazole molecules have indicated a design method beneficial for improved α-syn aggregate affinity [14,15]. With the aim to verify the design strategy with more scaffolds and to develop more brain-penetrant molecules for imaging α-syn aggregates in the brain, structurally diverse coumarin has attracted attention as an enticing scaffold, as coumarin serves as a substantial resource for the discovery of anti-neurodegenerative therapeutic drugs [16], and it represents an important chemical class of organic material for labeling biological molecules, owing to efficient brain distribution and dopaminergic/serotoninergic activities on the central nervous system [[16], [17], [18]]. The current work reports on the design and synthesis of novel compounds based on coumarin framework and biological evaluation towards α-syn aggregates in the brain.