Tau PET imaging: present and future directions

Abstract

Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3. These tracers are now available for clinical assessment in patients with various tauopathies, including Alzheimer's disease, as well as in healthy subjects. Exploring the patterns of tau deposition in vivo for different pathologies will allow discrimination between neurodegenerative diseases, including different tauopathies, and monitoring of disease progression. The variety and complexity of the different types of tau deposits in the different diseases, however, has resulted in quite a challenge for the development of tau PET tracers. Extensive work remains in order to fully characterize the binding properties of the tau PET tracers, and to assess their usefulness as an early biomarker of the underlying pathology. In this review, we summarize recent findings on the most promising tau PET tracers to date, discuss what has been learnt from these findings, and offer some suggestions for the next steps that need to be achieved in a near future.

Keywords: Biomarker; Clinical research; Neurodegenerative diseases; Positron emission tomography imaging; Tau; Tracer development.

Fig. 1

Tau pathology in relation to other pathological features in Alzheimer’s disease

Fig. 2

Number of publications on tau PET tracers in the recent years. The graph starts from the first publication on a tau tracer; each bar plot represents a period of three months

Fig. 3

Chemical structures of the main tau-specific radiotracers. [ ¹⁸ F]THK5117: 2-(4-methylaminophenyl)-6-[(3-[¹⁸ F]-fluoro-2-hydroxy)propoxy]quinoline; [ ¹⁸ F]THK5317: (S)-2-(4-methylaminophenyl)-6-[(3-[¹⁸ F]-fluoro-2-hydroxy)propoxy]quinoline; [ ¹⁸ F]THK5351: (S)-2-(4-methylaminopyridyl)-6-[(3-[¹⁸ F]-fluoro-2-hydroxy)propoxy]quinoline; [ ¹⁸ F]T808: 2-(4-(2-[¹⁸ F]-fluoroethyl)piperidin-1-yl)benzo[4, 5]imidazo[1,2-a]pyrimidine; [ ¹⁸ F]AV-1451: (7-(6- fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole; [ ¹¹ C]PBB3: (5-((1E,3E)-4-(6-[¹¹C]methylamino)pyridin-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-ol; [ ¹⁸ F]MK-6240: 6-([¹⁸ F]-fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine

Fig. 4

Comparison between [³H]THK5117 binding pattern using autoradiography and AT8 immunostaining. Experiments were performed on paraffin sections from the anterior part of the right hippocampus of a patient with pathologically confirmed AD. This figure was adapted from Lemoine et al., 2015 [24], with permission from the journal

Fig. 5

In vivo imaging of AD biomarkers in a patient with prodromal AD and in a patient with AD dementia. The retention of [¹⁸F]THK5317 and [¹¹C]PIB are expressed with reference to the retention in the grey matter of the cerebellum; [¹⁸F]FDG uptake is expressed with reference to uptake in the pons. AD = Alzheimer’s disease; DVR = distribution volume ratio; FDG = fluorodeoxyglucose; PIB = Pittsburgh compound B; SUVR = standardized uptake value ratio