Time for tau.

It is almost exactly 10 years since the first report of a PET ligand that specifically bound to a pathological protein in the brain was published (Klunk et al., 2004). This tracer, 11 C-Pittsburgh compound B (PIB), detected fibrillar aggregated forms of amyloid-b, the major constituent of the Alzheimer's disease plaque and, according to many, the initiating event in Alzheimer's disease patho-genesis. This report was soon followed by several amyloid imaging tracers that were radiolabelled with the longer half-life positron-emitting nuclide 18 F, opening the door to commercial manufacture and clinical application. Several of these tracers are now approved by worldwide regulatory agencies including the US Food and Drug Administration and the European Medicines Agency, although reimbursement for clinical use remains problematic. In this issue of Brain, Okamura and colleagues report the first human PET studies with a new tracer for tau, 18 F-THK5105, and reveal that retention of this tracer correlates with dementia severity and brain atrophy in Alzheimer's disease (Okamura et al., 2014). Because it is difficult to develop, test and validate a new PET imaging agent, it may have seemed overly optimistic 10 years ago to conclude that a new era in human brain imaging had begun, but it had. The latest developments are a series of PET tracers that bind to the microtubule-associated protein tau that is aggregated as neurofibrillary tangles in Alzheimer's disease. Tau-related diseases also include the group of tauopathies often referred to as frontotemporal lobar degenerations, and the highly publicized chronic traumatic encephalopathy. Tau would seem to be a difficult target for PET imaging: it may be intracellular thus requiring tracer passage across both the blood–brain barrier and cell membranes ; it is found in the brain at lower concentrations than amyl-oid-b; and it is characterized by different isoforms reflecting alternative splicing with either three (3R) or four (4R) repeated microtubule binding domains. The first PET tau imaging agent to be reported, 18 F-FDDNP, was not specific for tau and showed relatively low uptake. However, in the past few years, three research groups have investigated separate molecular structures resulting in three series of compounds that are promising tau-binding PET tracers. One of these, 11 C-PBB3 (Maruyama et al., 2013), has shown in vitro binding to tau in the form of neurofib-rillary tangles, neuropil threads and plaque neurites in Alzheimer's disease brain tissue, and also in vitro binding to tau inclusions in tissue from …