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      Small-Molecule PET Tracers for Imaging Proteinopathies

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      , PhD 1 , , MS 1 , , MD 2 , , MD, PhD 3
      Seminars in nuclear medicine

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          Abstract

          In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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          Author and article information

          Journal
          1264464
          7493
          Semin Nucl Med
          Semin Nucl Med
          Seminars in nuclear medicine
          0001-2998
          1558-4623
          7 July 2017
          13 July 2017
          September 2017
          01 September 2018
          : 47
          : 5
          : 553-575
          Affiliations
          [1 ]Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
          [2 ]Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA
          [3 ]Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
          Author notes
          Address correspondence to Chester A. Mathis, PhD, Department of Radiology, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213. mathisca@ 123456upmc.edu

          Address for proofs: Chester A. Mathis, PET Facility, B-938 UPMC Presbyterian Hospital, 200 Lothrop St, Pittsburgh, PA 15213, tel 412-647-0734; fax 412-647-0700; mathisca@ 123456upmc.edu

          Article
          PMC5657567 PMC5657567 5657567 nihpa890383
          10.1053/j.semnuclmed.2017.06.003
          5657567
          28826526
          b96d75f4-1ea4-4785-87fe-678285584a38
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