New tracers reveal fabric of tau proteins in Alzheimer’s disease pathology

Amyloid imaging has been the single stitch holding Alzheimer’s imaging together even though beta-amyloid plaque is typically interwoven in the brain with tangles of tau proteins, but that may soon change as two new tau radiotracers tighten the knit of novel dementia imaging, according to a study published July 15 in the Journal of Nuclear Medicine.

Nobuyuki Okamura, MD, from the department of pharmacology, Tohoku University School of Medicine, Sendai, Japan, and colleagues analyzed F-18 THK-5105 and F-18 THK-5117, both derivatives of arylquinoline, for their capability to point to tau protein in the brains of animal models with encouraging results, an important first step to developing a viable tau tracer.

“Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau,” wrote Okamura et al. “Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD.”

Progression of beta-amyloid burden and plaque deposition is thought to precede neurofibrillary tangles (NFT), composed of hyperphosphorylated tau, which is a microtubule-associated protein that secures the assembly of axonal microtubes. Tau accumulation is also recognized as dystrophic neuritis and neuropil threads in Alzheimer’s pathology.

“Phosphorylation of tau decreases its ability to bind to microtubules, which are destabilized, leading to neuronal death,” wrote the authors. “The deposition of NFTs is thought to begin before extensive neuronal loss and cognitive decline occur. Thus, noninvasive detection of tau pathology would be useful to predict future cognitive decline in the preclinical stages of AD and to track disease progression before extensive neuronal loss occurs.”

F-18 THK-5105 and F-18 THK-5117 are second-generation optimized compounds resulting from former research with F-18 labeled THK-523 (F-18 6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline).

For the purposes of this research, a toxicity study lasting 14 days was conducted by intravenous administration of the new compounds and binding affinity was assessed using synthetic tau aggregates in rats and mice. Homogenates of tau proteins were evaluated by binding assays and saturation. Pharmacokinetics of the tracer compounds were tested for biodistribution and binding selectivity to tau pathology was assessed with autoradiography of sectioned brain.

“In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates,” the researchers wrote. “Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of C-11 Pittsburgh compound B, showing preferential binding to amyloid plaques.”

The tracers showed successful brain uptake in mice with rapid wash out in controls and met the standards for PET imaging agents at an uptake of greater than 6 percent injected dose per gram of tissue at two minutes.

“F-18 THK-5105 and F-18 THK-5117 should be considered as promising candidates for PET tau imaging radiotracers,” wrote the authors. “Future clinical studies will clarify the usefulness of these radiotracers for the early detection of AD tau pathology.”