2. Academic Validation
  3. Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand

Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand

  • ACS Chem Neurosci. 2024 Nov 20;15(22):4210-4219. doi: 10.1021/acschemneuro.4c00493.
Dinahlee Saturnino Guarino 1,  Patricia Miranda Azpiazu 2,  Dan Sunnemark 3 4,  Charles S Elmore 5,  Jonas Bergare 5,  Markus Artelsmair 5,  Gunnar Nordvall 6,  Anton Forsberg Morén 2,  Zhisheng Jia 2,  Miguel Cortes-Gonzalez 2,  Robert H Mach 1,  Kyle C Wilcox 7,  Sjoerd Finnema 7,  Magnus Schou 8,  Andrea Varrone 2
Affiliations

Affiliations

  • 1 Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 2 Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, BioClinicum, Floor 4, Akademiska Stråket 1, 17174 Solna, Sweden.
  • 3 Offspring Biosciences, Sweden AB, SE-151 36 Södertälje, Sweden.
  • 4 Applied Immunology, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
  • 5 Isotope Chemistry, Drug Safety and Metabolism, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 6 AlzeCure Pharma AB, Hälsovägen 7, SE-141 57 Huddinge, Sweden.
  • 7 AbbVie Inc, 1 N Waukegan Road, North Chicago, Illinois 60064, United States.
  • 8 AstraZeneca, Precision Medicine Diagnostic Development and HBS Science, AstraZeneca R&DRINGGOLD Oncology, KI-RCF PET, J2:30, BioClinicum, Visionsgatan 4, SE-17164 Solna, Sweden.
PMID: 39528351 DOI: 10.1021/acschemneuro.4c00493
Abstract

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and Other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [11C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [11C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [11C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [11C]KAC-50.1 as a PET imaging agent.

Keywords

PET tracer; Parkinson’s disease; autoradiography; screening assays; α-synuclein.

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