New protein deposition tracers in the pipeline
© The Author(s) 2016
Received: 23 December 2015
Accepted: 13 May 2016
Published: 2 June 2016
Traditional nuclear medicine ligands were designed to target cellular receptors or transporters with a binding pocket and a defined structure–activity relationship. More recently, tracers have been developed to target pathological protein aggregations, which have less well-defined structure–activity relationships. Aggregations of proteins such as tau, α-synuclein, and β-amyloid (Aβ) have been identified in neurodegenerative diseases, including Alzheimer’s disease (AD) and other dementias, and Parkinson’s disease (PD). Indeed, Aβ deposition is a hallmark of AD, and detection methods have evolved from coloured dyes to modern 18F-labelled positron emission tomography (PET) tracers. Such tracers are becoming increasingly established in routine clinical practice for evaluation of Aβ neuritic plaque density in the brains of adults who are being evaluated for AD and other causes of cognitive impairment. While similar in structure, there are key differences between the available compounds in terms of dosing/dosimetry, pharmacokinetics, and interpretation of visual reads. In the future, quantification of Aβ-PET may further improve its utility. Tracers are now being developed for evaluation of tau protein, which is associated with decreased cognitive function and neurodegenerative changes in AD, and is implicated in the pathogenesis of other neurodegenerative diseases. While no compound has yet been approved for tau imaging in clinical use, it is a very active area of research. Development of tau tracers comprises in-depth characterisation of existing radiotracers, clinical validation, a better understanding of uptake patterns, test-retest/dosimetry data, and neuropathological correlations with PET. Tau imaging may allow early, more accurate diagnosis, and monitoring of disease progression, in a range of conditions. Another marker for which imaging modalities are needed is α-synuclein, which has potential for conditions including PD and dementia with Lewy bodies. Efforts to develop a suitable tracer are ongoing, but are still in their infancy. In conclusion, several PET tracers for detection of pathological protein depositions are now available for clinical use, particularly PET tracers that bind to Aβ plaques. Tau-PET tracers are currently in clinical development, and α-synuclein protein deposition tracers are at early stage of research. These tracers will continue to change our understanding of complex disease processes.
KeywordsPET Radiotracer Beta-amyloid Tau Alpha-synuclein Neurodegeneration
Traditionally, nuclear medicine ligands were primarily designed for targeting cellular receptors or transporters. They were tightly bound, and often internalized or transported into the cell and trapped inside by metabolic transformation, while unbound ligand was cleared. More recently, a class of imaging tracers has become available whose members bind misfolded protein aggregates. This new paradigm requires different lead optimization, different types of analysis, and quantitation. Previous approaches targeted a binding pocket where derivatives of ligands displayed a defined structure-activity relationship. Examples of protein aggregate imaging include Aβ, tau, and α-synuclein. Such investigations required the design of a molecule that binds to β-sheets. The structure–activity relationship is less well defined, as no distinct binding pockets are present. Importantly, all protein depositions show a similar structural motif, and achievement of selectivity is the most important optimization goal. Nonetheless, protein sequence and aggregate structures are different enough that highly specific imaging agents have been developed for some of these targets.
Co-pathologies have also been observed, in which more than one protein forms a deposition. Identification of in vivo biomarkers for such conditions will improve diagnosis and classification of patients, provide prognostic information, and improve the efficiency of drug development. This paper will discuss some of the new positron emission tomography (PET) tracers that are being developed to target misfolded protein depositions such as Aβ, tau, and α-synuclein.
Established protein tracers–detection of Aβ plaques
AD is a chronic neurodegenerative disease that can now be detected in vivo by biomarkers years before clinical manifestation. The deposition of Aβ plaques is considered one hallmark in the pathogenesis of AD, and a hypothetical model of biomarker temporal evolution has been proposed that matches the sequence of molecular events proposed in the amyloid cascade hypothesis (Jack & Holtzman 2013). The model begins with Aβ42 overproduction and aggregation, with decreased clearance, followed by plaque formation. Thus Aβ-PET and cerebrospinal fluid (CSF) Aβ42 levels are the first markers to become abnormal in AD pathogenesis, although these biomarkers are not approved for prediction of disease progression or therapeutic monitoring.
Overview Aß tracers
[11C]-PiB (Klunk et al. 2004)
[18F]-flutemetamol (VizamylTM) (GE Healthcare 2014)
• Approved for clinical use
• Injected dose: 185 MBq
• Effective dose: 5.9 mSv (32 μSv/MBq)
• Imaging window: 90-110 min p.i.
• Scan duration: 20 min
• Visual assessment: color
[18F]-NAV4694 (formerly AZD4694) (Cselényi et al. 2012)
[18F]-florbetaben (NeuraCeqTM) (Piramal Imaging 2014)
• Approved for clinical use
• Injected dose: 300 MBq
• Effective dose: 5.8 mSv (19 μSv/MBq)
• Imaging window: 90-110 min p.i.
• Scan duration: 20 min
• Visual assessment: grey scale
[18F]-florbetapir (AmyvidTM) (Eli Lilly 2013)
• Approved for clinical use
• Injected dose: 370 MBq
• Effective dose: 7.0 mSv (19 μSv/MBq)
• Imaging window: 30-50 min p.i.
• Scan duration: 10 min
• Visual assessment: grey scale
The three approved agents have a planar chemical structure that is suitable for binding to β-sheets in Aβ plaques. All approved agents follow the same mechanism of binding, but their different chemical structures lead to differences with regard to dosing and dosimetry; pharmacokinetics, including partitioning into grey and white matter structures; and interpretation of visual reads (Eli Lilly 2013; Piramal Imaging 2014; GE Healthcare 2014). For example, 18F-florbetapir and 18F-florbetaben PET images are approved for evaluation in greyscale, while 18F-flutemetamol PET images are read using a colour scale when used in the clinical setting. Thus each tracer requires a unique medical education programme to ensure reliable assessment of scans and to distinguish uptake in white matter from cortical grey matter.
Regulatory approval for Aβ PET scan assessment is currently based solely on a binary visual read-out, and all three reading methods have been validated against histopathology (Clark et al. 2012; Curtis et al. 2015; Sabri et al. 2015a). Of note, imaging agents used in oncology such as 18F-FDG or 18F-FLT become trapped in tumours leading to a stable or even increasing signal over time (Shields et al. 1998). In Aβ imaging, however, the tracer instead shows decreasing signal or standardised uptake values (SUVs) over time, as a result of washout after binding to Aß plaque-affected cortical areas. In addition, quantification of Aβ-PET scans typically involves calculating the SUV ratio, where the reference region is a region with a ligand uptake and washout pattern similar to Aß-plaque-affected cortical areas regardless of whether Aβ plaques are present (Schmidt et al. 2015). A number of different reference regions have been proposed (Landau et al. 2015), but further discussion is outside the scope of this review. Quantification of PET scans has the ability to better detect longitudinal changes during therapeutic intervention and has the potential for automated analysis via software with more detailed regional analysis. Future uses of Aβ-PET quantification, though not approved for routine clinical use, may include improved assessment in uncertain clinical cases, drug trial enrichment by patient selection, pre-symptomatic staging of disease, and therapeutic monitoring. Such uses require robust longitudinal assessment, reliable reference-region validation, and standardisation.
Beyond AD, amyloid-PET provides a unique opportunity for in vivo research of other conditions that are present with Aβ deposition. For example, Aβ-PET may also detect other plaque types and states of amyloid (e.g. diffuse plaques) (Sabri et al. 2015b), and thus may provide additional insights into the disease and its pathogenesis. Other conditions with Aβ-plaque depositions are reported, such as Lewy body diseases, cerebral amyloid angiopathy, brain trauma, and Down syndrome. As specific as the current tracers are for Aβ over other misfolded protein aggregates, somewhat surprisingly they do bind other amyloids outside the brain. 18F-Florbetaben and 18F-florbetapir have been reported to bind amyloid deposits in cardiac amyloidosis (Dorbala et al. 2014; Catafau & Bullich 2015; Mollee et al. 2015), and these tracers are also hypothesized to bind other peripheral amyloid deposits. In addition, tracers may also have value as a myelin biomarker in conditions such as multiple sclerosis (Matías-Guiu et al. 2015), by virtue of their white-matter signal.
Protein deposition tracers under development
Detection of tau protein
Tau protein is the name given to soluble microtubule-associated protein (MAP), which is essential for regulating intracellular transport (Spillantini & Goedert 2013). Six different isoforms of tau exist, which can be distinguished by their number of binding domains (either three or four), and different forms are accumulated in different diseases (Delacourte 1999; Braak & Braak 1998). Furthermore, hyperphosphorylation and other post-translational modifications can have an impact on tau conformation, leading to, for example, aggregation in filamentous structures.
Tau protein aggregation leads to neuronal cell dysfunction and death, and studies show a strong association between tau deposits, decreased cognitive function, and neurodegenerative changes in AD. While the evolution of AD neuropathology depends on interactions between Aβ and tau (Jucker & Walker 2011), the relative contributions of the two proteins in the development of AD remain unclear. There is emerging evidence from studying hereditary Alzheimer’s Disease (e.g. DIAN study) that continues to point to a primary role of Aß in AD. Significant proportions of the observed variance in age at symptom onset can be explained by family history and mutation type (Ryman et al. 2014). Nevertheless, several other questions remain including the presence of Aβ deposition in cognitively normal individuals and time to development of first symptoms or the weak correlation between plaque load and cognition (Morris et al. 2014). Expanding the view of the AD pathogenesis beyond Aβ and tau pathology and considering aspects such as lifestyle, cognitive reserve may provide answers in the future. Imaging Aß and tau allows investigators to look at the impact on cognition and follow subjects from an earlier stage. In addition to AD several neurodegenerative diseases – including chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, and some variants of frontotemporal lobar degeneration – have been described in which tau aggregate deposition is a dominant pathology (Mohorko & Bresjanac 2008; Lee et al. 2001; McKee et al. 2009).
Tau is a more complex target than Aβ in that the monomer protein is much larger than Aβ, is represented in different isoforms in different diseases, is present in lower amounts and has a distinct anatomic spread throughout the brain as the different diseases progress. These characteristics, and the intracellular localisation, make the requirements for a tau PET tracer more challenging (Villemagne et al. 2015).
Characteristics of published tau protein tracers updated from (Villemagne et al. 2015)
• Selectively binds to tau
• Retention of 11C-PBB3 in the venous sinuses
• Retention of tracer in basal ganglia in patient with corticobasal degeneration suggests that it might bind to non-AD tauopathies
• First 18F-tracer with tau binding
• Lack of selectivity for tau; nanomolar binding affinity to Aβ
• Very limited dynamic range
• Regional brain retention used for differentiating Aβ and tau
• In vitro binding to paired helical filament-tau demonstrated
• No brain uptake in mice (P-glycoprotein substrate)
• Brain uptake in non-human primates
• No human studies reported
[18F]-N-Methyl-Lansoprazole (Fawaz et al. 2014)
[18F]-THK-523 (Harada et al. 2013)
• Slow kinetics
• Non-specific binding (white matter, brain stem)
• No detection of non-AD tauopathies (Pick’s disease; three-repeat tauopathy)
• Faster kinetics and higher contrast than 18F-THK-523
• Non-specific binding (white matter, brain stem)
[18F]-THK-5351 (Harada et al. 2015)
• Faster kinetics and higher contrast than THK-523
• Lower white matter retention
• Higher signal-to-noise ratio compared with 18F-THK-5105 and 18F-THK-5117
6,5,6 Tricyclic pyrimidines and indoles
• Tracer with broadest clinical data package
• Cortical retention consistent with the known distribution of tau in AD brain
• Strong correlation with disease severity
• Slower kinetics than 18F-T808
• Off-target activity (striatum, choroid plexus)
[18F]-T808 (Chien et al. 2014)
• Faster kinetics than 18F-T807
• Substantial defluorination
[18F]-MK-6240 (Walji et al. 2016)
• Good in vitro binding affinity to NFTs, high selectivity to β-amyloid, and excellent physicochemical properties for brain penetration and cellular permeability.
• No off-target binding and suitable in vivo pharmacokinetics
• Clinical studies are currently underway
Future development of tau tracers will require further evaluation of existing radiotracers, including preclinical characterisation, validation in the clinic, better understanding of uptake patterns in healthy controls, test-retest and human dosimetry data, and neuropathological correlations with PET, as well as head-to-head comparisons between different tracers. Improvement seems possible in the pharmacokinetic properties of 18F-labeled tracers, binding selectivity, and experience in non-AD tauopathies.
Overall, the combination of Aβ and tau-PET is currently significantly improving the knowledge of the interactions between the two proteins in humans. In addition, tau-PET–in its unique role as a marker of neurodegeneration–may allow the in vivo study of tau pathology evolution and topographic distribution across diseases. Tau imaging could also allow early, more accurate diagnosis, and more importantly monitoring of disease progression, in other tauopathies, cognitive impairment, movement disorders, and head trauma. Tau-PET may also lead to more efficient development of disease-modifying drugs not only for compounds targeting the tau protein itself.
Detection of α-synuclein
Investigation of α-synuclein and TDP-43 in post-mortem human brains has led to increased understanding of the evolution of neuropathology in PD and amyotrophic lateral sclerosis, in which lesions are believed to spread from an initial ‘seed’ of misfolded protein (Jucker & Walker 2013). There is therefore a clinical need for imaging modalities for detection of α-synuclein, which has a potential role in the differential diagnosis of PD, dementia with Lewy bodies, progressive supranuclear palsy, and multiple system atrophy. Genetic biomarkers in these conditions, while critically important in the case of inherited disease, are not salient in the majority of cases (>90 %) with sporadic PD. Detection methods for α-synuclein in CSF are currently under development, although it is not clear how CSF levels relate to histopathology data (Mollenhauer 2014) and still need further validation.
Characteristics of published a-synuclein deposition tracers
[11C] BF-227 (Kikuchi et al. 2010)
• Non-selective, affinities: see below for 18F-derivative
• Investigated in MSA patients
[18F] BF-227: (Fodero-Tavoletti et al. 2009)
• Aß1-42 fibrils: KD1 = 1.3 nM
• α-syn fibrils: KD = 9.6 nM
SIL23 (Bagchi et al. 2013)
• Affinity and selectivity not optimal for in vivo imaging
• Affinity α-synuclein: Ki = 58 nM
• Screening tool
[18F] 2b (Zhang et al. 2014)
• Affinity α-synuclein: Ki = 49 nM
• Selectivity α -syn vs. Aß: 2-fold
• Selectivity α -syn vs. tau: 2.5-fold
• Crosses blood–brain-barrier in healthy cynomolgus macaques
• Shows sufficient initial uptake and wash-out
• Higher selectivity desired
[11C] 2a (Zhang et al. 2014)
• Affinity α-synuclein: Ki = 32 nM
• Selectivity α-syn vs. Aß: 3-fold
• Selectivity α-syn vs. tau: 4-fold
• Crosses blood–brain-barrier in cynomolgus macaques
• Shows sufficient initial uptake and wash-out
• Higher selectivity desired
3-(Benzylidene) indolin-2-one derivatives
[18F] 46a: (Chu et al. 2015)
• Selective for α-synuclein:
o α-syn Kd = 8.9 nM
o Aß Kd = 271 nM
o Tau fibrils: 50 nM
• High logP and presence of nitro group may limit its use for in vivo PET studies
• Potential as secondary lead compound for further SAR studies
A series of phenothiazine derivatives was described for α-synuclein-binding (Yu et al. 2012) and the radioiodinated compound SIL23 was developed (Bagchi et al. 2013). As stated by its developers, the affinity of SIL23 for α-synuclein and its selectivity for α-synuclein versus Aβ and tau fibrils is not optimal for imaging fibrillar α-synuclein in vivo, but it could be used to screen additional ligands for suitable affinity and selectivity. Following this approach, additional compounds such as [11C] 2a and [18F] 2b have been identified that are more specific for α-synuclein and have shown the ability to cross the blood–brain barrier in animal studies (Zhang et al. 2014). However, these have not yet translated to human imaging. More recently, the same group reported the development and in vitro characterization of (benzylidene) indolin-2-one derivatives as new ligands for α-synuclein fibrils covering also PET ligands like [18F] 46a with high affinity and selectivity for α-synuclein (Chu et al. 2015). Future research will show whether some of these compounds have the ability to image α-synuclein depositions in patients.
Several PET tracers for detection of pathological protein depositions or aggregates are now available for routine clinical use. In particular, PET agents binding to Aβ plaques are approved as an adjunct to other diagnostic evaluations to estimate the plaque density in patients with cognitive impairment who are being evaluated for AD or other causes of cognitive decline. Tau-PET tracers are currently in clinical development, and α-synuclein protein deposition tracers are at early stage of research. Importantly, PET tracer development and imaging of protein aggregates require different approaches to those involved in imaging of receptors or transporters, including lead optimisation, scan analyses and quantitation. These tracers have, and will continue to, change our understanding of complex disease processes.
Positron emission tomography
Standardized uptake value
43 kDa Tar DNA-binding protein
Beta-amyloid beta (1–42)
Medical writing assistance was provided by Dan Booth PhD (Bioscript Medical Ltd) and funded by Piramal Imaging GmbH, Berlin, Germany. Histopathology images of TDP-43 inclusions, Tau tangles and Aβ deposits were kindly provided by Professor Walter Schulz-Schaeffer (Goettingen, Germany).
AJ, NK, AM, and AS developed the presentation on which this manuscript is based, and were involved in the drafting and final approval of the manuscript. All authors read and approved the final manuscript.
AJ is an employee of Piramal Imaging GmbH, Berlin. NK, AM, and AS are employees of, and holds property rights/patents for (radio) pharmaceuticals with, Piramal Imaging GmbH, Berlin.
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