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Synucleinopathies comprise a family of high prevalence adult-onset neurodegenerative disorders primarily characterized by the appearance of intraneuronal Lewy bodies (LBs) composed of aggregated forms of α-synuclein (αSyn) protein. A long-term goal of the field is to develop positron emission tomography (PET) imaging agents capable of detecting and staging synucleinopathies in living cases. Although many candidate radiotracers have been developed for imaging cross-β-sheet aggregates in neurodegenerative disease, the mechanisms that mediate their high affinity binding (i.e., low nM) to the surfaces presented by αSyn, tau, or β-amyloid are not fully understood. Understanding small molecule binding to αSyn aggregates is of particular interest as a successful radiotracer has yet to be developed and could revolutionize disease diagnosis. To better understand the binding mechanism, we began by preparing a library of small molecule ligands through chemical synthesis. The library was screened against synthetic αSyn aggregates via thioflavin dye displacement, resulting in the identification of several high affinity ligands (2 - 20 nM). To directly quantify their binding to synthetic aggregates, a candidate ligand was tritiated via a four-step synthesis procedure yielding a direct binding radioligand. Radioassays with the ligand, [3H]CC05-61, confirmed high affinity (Kd = 6.4 nM) and high occupancy binding for αSyn, resulting in the highest binding efficiency (defined as binding site density/affinity) for any synthetic aggregate reported to date. To identify the sites responsible for high affinity binding, three distinct analytical approaches were taken. First, a simple model of cross-β-sheet aggregate surfaces was created from the amyloidogenic hexapeptide sequence, VQIVYK, by introducing substitutions at the Q2 and V4 positions. Results from this model identified channels flanked by Lys, Gly, Ser, and Phe residues as being supportive of high affinity ligand binding. Second, Rosetta-based docking was performed on the Polymorph 1a synthetic aggregate structure of αSyn (PDB: 6H6B). Five binding sites were found on this polymorph, one of which demonstrated cation-π binding at the K58/60 double Lysine sequence motif. Finally, Lys-to-Ala mutagenesis of αSyn was performed to test the contribution of Lysine pairs to binding affinity. [3H]CC05-61 displacement radioassays with K43/45A, K58/60A, and K96/97A αSyn mutants demonstrated a depression in binding signal in the K58/60A mutant. Together, these findings point toward cation-π binding as one mode of interaction capable of supporting high affinity binding to synthetic αSyn aggregates. Because the double Lysine sequence motif is repeated within αSyn and exposed to solvent in at least one position of all αSyn polymorphs characterized to date, the cation-π binding mechanism identified here may provide a route toward a high affinity, high binding site density, and pan-polymorph specific αSyn-aggregate imaging agent.