Tau imaging: A review of the triumphs and challenges

Tau has been identified as one of the keys to unlocking neurodegenerative disease, including Alzheimer’s. However, efforts to develop an ideal tau PET agent continue to be an uphill battle, according to a review published May 15 in the Journal of Nuclear Medicine.

Tau stands for tubulin-associated unit, an intracellular protein that binds and secures axonal microtubules within neurons. It plays an essential role in regulating intracellular transport. Recently researchers have discovered, much like beta-amyloid, it also plays a role in the pathology of dementia.

Maliha Shah and Ana M. Catafau, MD, PhD, both investigators for the department of clinical research and development in neurosciences Piramal Imaging in Germany, reviewed the sticking points and all of the potential tracers in the pipeline.

The necessities of a tau tracer including the ability to cross both the blood-brain barrier and individual neuronal cell membranes; the capacity to seek out and bind to the deposition of all six isoforms of tau; and because tau aggregates can be found in white-matter, binding in this area should be specific and informative. Lastly, due to the complex interplay and fluctuation of protein deposits in the brain, a tau tracer must be incredibly selective and have strong affinity for desired targets.  

“For this reason, experiments should ideally be performed on human brain slices rather than on recombinant tau fibrils, which lack various posttranslational modifications and other morphologic aspects of in vivo tau deposits,” wrote Shah and Catafau.

F-18 FDDNP came on the scene as the initial tau PET tracer, but upon further research it was found to bind to beta-amyloid as well as a-synuclein and was not specific enough. Alternatives still in investigation include C-11 N-methyl lansoprazole, FDA approved but no human studies have been completed thus far; C-11 PBB3, which shows great promise and also indicates other disease processes like corticobasal syndrome, but its short half-life is seen as a limitation; F-18 THK523 showed some successful, but binds to white matter and does not bind to all tau lesions; F-18 THK5105 and F-18 K5117 appear to do the trick according to trial data limited to recombinant and small animal data, but further research is required; F-18 T808 and T807 bind strongly and have proven to be high selective when differentiating tau from amyloid, but T808 also binds to bone and only a small study of six subjects has have been presented for T807. However, the latter does appear to be a contender.

“In conclusion, the hunt for a tau tracer that overcomes all these challenges is considerably more daunting than appears at first sight,” the researchers wrote. “Nevertheless, considerable progress has been made and several ligands have entered human imaging studies.”