Small-molecule PET Tracers for Imaging Proteinopathies

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.

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…Specific high-affinity ligands for misfolded a-synuclein pathology suitable for brain imaging have been difficult to identify [125,126]. SIL23 is not sufficiently selective in the presence of Ab or tau pathology.…”

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…Other studies also support that moderate to frequent striatal (and cortical) diffuse Aβ plaques are PET detectable (Beach, Thal, Zanette, Smith, & Buckley, ). For a more in‐depth review of amyloid PET imaging in AD the reader is referred to Mathis, Lopresti, Ikonomovic, & Klunk, .…”

“…Studies of DS also reported accumulation of alpha‐synuclein aggregates in Lewy bodies and neurites in neocortex and amygdala (Davidson et al, ; Lippa, Schmidt, Lee, & Trojanowski, ) and TDP‐43 in dentate gyrus granule cells (Davidson et al, ; Lippa et al, ). Though none of currently available amyloid PET ligands binds to tau, alpha‐synuclein, or TDP‐43 aggregates, the relationship of these lesions to amyloid is an important avenue of investigation, in relation to development of dementia in people with DS, especially if PET ligands specific for alpha‐synuclein and TDP‐43 are developed successfully (Mathis et al, ).…”

Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

“…However, unlike Alzheimer's disease, where similar observations have inspired the initiation of “prevention” trials in individuals either genetically at risk (DIANE) or bearing imaging evidence of brain amyloid pathology (A4), prodromal PD is characterized by an accumulation of relatively nonspecific and unrelated symptoms and signs such as hyposmia, rapid eye movement sleep behavior disorder, and autonomic dysfunction, thus making recognition of the prodromal PD difficult in the general practice environment. Furthermore, we lack a biomarker of PD pathology that has the discriminative and predictive abilities of amyloid PET imaging . To enable the conduct of true prevention trials in PD, not only do we need strongly predictive biomarkers but also we need to educate general internal medicine, geriatric, and primary care physicians as well as the lay community about the importance of recognizing prodromal PD.…”

“…13,14 A second major challenge is that there currently is no established method to assess target engagement in the brain for therapies that target a-synuclein. [15][16][17] The key species of a-synuclein aggregates that is pathogenic and causes neurodegeneration remains to be established, and consequently, it is unknown if a FIG. 1.…”