Abstract The development of imaging agents for in vivo detection of alpha‐synuclein (α‐syn) pathologies faces several challenges. A major gap in the field is the lack of diverse molecular scaffolds with high affinity and selectivity to α‐syn fibrils for in vitro screening assays. Better in vitro scaffolds can instruct the discovery of better in vivo agents. We report the rational design, synthesis, and in vitro evaluation of a series of novel 1‐indanone and 1,3‐indandione derivatives from a Structure‐Activity Relationship (SAR) study centered on some existing α‐syn fibril binding ligands. Our results from fibril saturation binding experiments show that two of the lead candidates compounds 8 and 32 bind α‐syn fibrils with binding constants (K d ) of 9.0 and 18.8 nM, respectively, and selectivity of greater than 10× for α‐syn fibrils compared with amyloid‐β (Aβ) and tau fibrils. Our results demonstrate that the lead ligands avidly label all forms of α‐syn on PD brain tissue sections, but only the dense core of senile plaques in AD brain tissue, respectively. These results are corroborated by ligand‐antibody colocalization data from Syn211, which shows immunoreactivity toward all forms of α‐syn aggregates, and Syn303, which displays preferential reactivity toward mature Lewy pathology. Our results reveal that 1‐indanone derivatives have desirable properties for the biological evaluation of α‐synucleinopathies.