The similarities between
11C-PBB3 and
11C-AZD2184 in terms of regional distribution, especially in the temporal lobe, as well as the very strong regional correlations in tracer binding could potentially raise the question as to the molecular target of
11C-PBB3. Furthermore, the facts that
11C-PBB3 and
11C-AZD2184 have similar chemical structures, although the linker domains differ in length, and have common off-target signals in the dural venous sinuses, add to this uncertainty. Similarities in the molecular targets of
11C-PBB3 and
11C-AZD2184 indicate limited specificity of
11C-PBB3 for tau and a potential binding affinity of the tracer for the more abundant (in the AD brain) amyloid-beta. However, early in vitro evidence to date excludes this possibility [
9], although more detailed in vitro competition studies are lacking for further validating the tracer specificity. Additionally, an earlier study that focused on a generally older, more severely affected sample of patients did not show a relationship between
11C-PBB3 binding and amyloid-beta burden globally, indicating that the latter relationship could occur only in the early stages of the disease or in distinct brain regions [
10]. Indeed, in our study, the regional correlations between
11C-PBB3 and
11C-AZD2184 binding were limited to the temporal and occipital lobes. The latter areas are well known as the richest areas for neuritic plaques [
41] (i.e. dense-core amyloid-beta plaques surrounded by tau-rich dystrophic neurites [
42]) in the AD brain. Based on this evidence, it is conceivable that
11C-PBB3 binds preferentially to tau deposits located in close proximity to the abundant amyloid-beta plaques in the early symptomatic stages of AD examined in this study, while
11C-THK5351 appears to bind to a wider range of tau deposits [
43], based on the regional distribution of the tracer. This hypothesis, however, remains to be proven with thorough ante-/post-mortem investigations.