11 C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson's Disease That Binds to α-Synuclein Fibrils in vitro and Crosses the Blood-Brain Barrier.

There is an urgent clinical need for imaging of alpha-synuclein (alphaSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of alphaSyn are rare. Diphenyl pyrazoles are known modulators of alphaSyn aggregation and thus bear potential for non-invasive detection of this biomarker in vivo. Here we demonstrate high-affinity binding of the family member anle253b to fibrillar alphaSyn and present a high-yielding site-selective radiosynthesis route for (11) C radiolabeling using in-situ generated [(11) C]formaldehyde and reductive methylation. Radio-HPLC of the tracer after incubation with rat serum in vitro shows excellent stability of the molecule. Positron emission tomography in healthy animals is used to assess the pharmacokinetics and biodistribution of the tracer, showing good penetration of the blood-brain barrier and low background binding to the non-pathological brain.