AZD-2184

Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (¹¹C-THK5351 and ¹¹C-PBB3) in a head-to-head, in vivo, multimodal design.

Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers ¹¹C-THK5351 and ¹¹C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer ¹¹C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.

The load and regional distribution of binding differed between ¹¹C-THK5351 and ¹¹C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of ¹¹C-PBB3, but not that of ¹¹C-THK5351, in the temporal lobe resembled that of ¹¹C-AZD2184, with strong correlations detected between ¹¹C-PBB3 and ¹¹C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with ¹¹C-THK5351 than with ¹¹C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with ¹¹C-THK5351 than with ¹¹C-PBB3 binding.

This research suggests different molecular targets for these tracers; while ¹¹C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of ¹¹C-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the β region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid β fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the ¹¹C-Pittsburgh Compound B (¹¹C-PIB). However, for in vitro conditions, significant binding of ³H-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid β fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.