The potential benefits of developing a PET agent capable of imaging alpha synuclein (a-syn) inclusions are severalfold, as has been seen in the Alzheimer’s field with the success of amyloid- and tau-PET measures. A reliable a-syn PET tracer would support differential diagnosis of synucleinopathies, aid trial enrolment and stratification, and enable response monitoring of candidate therapeutic agents targeting a-syn. Francesca Capotosti, PhD, AC Immune SA, Lausanne, Switzerland, discusses the challenges in the development of an a-syn PET tracer and introduces [18F]ACI-12589 as a novel candidate. Following its discovery, ACI-12589 underwent medicinal chemistry optimization, off-target activity assessment, and pharmacokinetic evaluation. Compelling preclinical evidence led to a first-in-human study in synucleinopathy subjects and controls. ACI-12589 shows high-affinity binding to pathological a-syn, with uptake patterns matching the brain areas known to be affected by the disease process based on clinical manifestations. Additionally, signal separation was noted in the multiple systems atrophy (MSA) cohort, compared to controls and other synucleinopathies. The tracer was also able to discriminate between MSA-C and MSA-P. Further investigation is needed to characterize how the PET signal evolves longitudinally and how early a change can be detected. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.