11C 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

• Published in: ChemMedChem Vol. 15; no. 5; pp. 411 - 415
• Main Authors: Maurer, Andreas, Leonov, Andrei, Ryazanov, Sergey, Herfert, Kristina, Kuebler, Laura, Buss, Sabrina, Schmidt, Felix, Weckbecker, Daniel, Linder, Ruth, Bender, Dirk, Giese, Armin, Pichler, Bernd J., Griesinger, Christian
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 05.03.2020; John Wiley and Sons Inc
• Subjects: Binding; Biomarkers; Blood; Blood-brain barrier; Brain; Communication; Communications; diphenylpyrazoles; Emission analysis; Fibrils; High-performance liquid chromatography; Incubation; Liquid chromatography; Medical imaging; Methylation; Modulators; Movement disorders; Neurodegenerative diseases; Neuroimaging; Neuromodulation; Parkinson's disease; Pharmacokinetics; Positron emission; Positron emission tomography; Pyrazoles; Radiolabelling; radiotracers; Route selection; Synuclein; Tomography; α-synuclein
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900689

There is an urgent clinical need for imaging of α‐synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn 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 αSyn and present a high‐yielding site‐selective radiosynthesis route for 11C radiolabeling using in‐situ generated [11C]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. High binding, low background: Development of radiotracers for α‐synuclein has proven challenging. Herein we describe a radiolabeling strategy for the aggregation modulator anle253b (2) and demonstrate its successful penetration of the blood‐brain barrier in healthy rats as well as its high‐affinity binding to aggregated α‐synuclein in vitro.