PURPOSE: The goal was to identify molecular imaging probes that would enter the brain, selectively bind to Parkinson's disease (PD) pathology, and be detectable with one or more imaging modalities. PROCEDURE: A library of organic compounds was screened for the ability to bind hallmark pathology in human Parkinson's and Alzheimer's disease tissue, alpha-synuclein oligomers and inclusions in two cell culture models, and alpha-synuclein aggregates in cortical neurons of a transgenic mouse model. Finally, compounds were tested for blood-brain barrier permeability using intravital microscopy. RESULTS: Several lead compounds were identified that bound the human PD pathology, and some showed selectivity over Alzheimer's pathology. The cell culture models and transgenic mouse models that exhibit alpha-synuclein aggregation did not prove predictive for ligand binding. The compounds had favorable physicochemical properties, and several were brain permeable. CONCLUSIONS: Future experiments will focus on more extensive evaluation of the lead compounds as PET ligands for clinical imaging of PD pathology.
PURPOSE: The goal was to identify molecular imaging probes that would enter the brain, selectively bind to Parkinson's disease (PD) pathology, and be detectable with one or more imaging modalities. PROCEDURE: A library of organic compounds was screened for the ability to bind hallmark pathology in humanParkinson's and Alzheimer's disease tissue, alpha-synuclein oligomers and inclusions in two cell culture models, and alpha-synuclein aggregates in cortical neurons of a transgenic mouse model. Finally, compounds were tested for blood-brain barrier permeability using intravital microscopy. RESULTS: Several lead compounds were identified that bound the human PD pathology, and some showed selectivity over Alzheimer's pathology. The cell culture models and transgenic mouse models that exhibit alpha-synuclein aggregation did not prove predictive for ligand binding. The compounds had favorable physicochemical properties, and several were brain permeable. CONCLUSIONS: Future experiments will focus on more extensive evaluation of the lead compounds as PET ligands for clinical imaging of PD pathology.
Authors: William E Klunk; Henry Engler; Agneta Nordberg; Brian J Bacskai; Yanming Wang; Julie C Price; Mats Bergström; Bradley T Hyman; Bengt Långström; Chester A Mathis Journal: Neuroimaging Clin N Am Date: 2003-11 Impact factor: 2.264
Authors: Chester A Mathis; Yanming Wang; Daniel P Holt; Guo-Feng Huang; Manik L Debnath; William E Klunk Journal: J Med Chem Date: 2003-06-19 Impact factor: 7.446
Authors: Wenhua Chu; Dong Zhou; Vrinda Gaba; Jialu Liu; Shihong Li; Xin Peng; Jinbin Xu; Dhruva Dhavale; Devika P Bagchi; André d'Avignon; Naomi B Shakerdge; Brian J Bacskai; Zhude Tu; Paul T Kotzbauer; Robert H Mach Journal: J Med Chem Date: 2015-07-31 Impact factor: 7.446
Authors: Zsofia Lengyel-Zhand; John J Ferrie; Bieneke Janssen; Chia-Ju Hsieh; Thomas Graham; Kui-Ying Xu; Conor M Haney; Virginia M-Y Lee; John Q Trojanowski; E James Petersson; Robert H Mach Journal: Chem Commun (Camb) Date: 2020-03-24 Impact factor: 6.222