New protein deposition tracers in the pipeline

Abstract

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.

Keywords: Alpha-synuclein; Beta-amyloid; Neurodegeneration; PET; Radiotracer; Tau.

Fig. 1

Schematic summary of key proteins present in frontotemporal lobar degeneration, Alzheimer’s disease, diffuse Lewy body disease and Parkinson disease. Protein monomers and their distribution for different clinical phenotypes are illustrated with symbolic drawings. Exemplary histopathology images are presented for TDP-43 inclusion, neurofibrillary tau tangles (immunohistochemistry with antibody AT8), amyloid-beta deposition (immunohistochemistry with monoclonal 6E10 Aβ antibody), and α-synuclein Lewy body inclusions (Images of TDP-43 inclusions, tau tangles, and Aβ deposits courtesy of Walter Schulz-Schaeffer, Goettingen, Germany)