As if to ensure that nobody would leave early, the 6th Human Amyloid Imaging Conference, held on 12-13 January 2012 in Miami, Florida, held until the very end the agenda item that had inspired the most advance speculation and curiosity. The last two talks of the Conference were about efforts to fill a gaping void in AD imaging, that is, to develop a PET agent that will visualize the other pathologic lesion as defined by Alois Alzheimer. “A tau imaging agent might provide the missing link between Aβ pathology and neurodegeneration,” said Victor Villemagne of the University of Melbourne, Australia. The Conference up to this point had highlighted how visualizing but one of a number of proteins that together wreak havoc in the aging brain gets the field only so far (see Part 8 of this series).

Why have tau PET ligands been more elusive than Aβ ligands? It is not for lack of trying, scientists said. Tau is a difficult target for a tracer to find because its concentration in the brain is manifold lower than that of Aβ, and it is primarily intracellular. What’s worse, its many isoforms, post-translational modifications, and conformations make it quite the dizzying target. At HAI, Villemagne and Hartmut Kolb of Siemens Inc., in Culver City, California, each introduced a candidate tau ligand. One appears to offer proof of principle in humans, though less impressively than did PIB, and the other is a preclinical alternative poised to show its mettle in first human experiments this spring. First, the more advanced agent.

Villemagne, for the first time, showed human PET data of the tau radioligand 18F THK523. Scientists at Tohoku University in Sendai, Japan, have been developing THK523 since 2002 and, in collaboration with Villemagne’s group, recently reported that it binds tau selectively in tissue sections (Fodero-Tavoletti et al., 2011). The human volunteers presented at HAI constitute the first eight enrollees of a study calling for 35 people in all. Three have moderate Alzheimer’s; three have semantic dementia, a form of FTLD devoid of amyloid β and tau deposition; and two were cognitively normal elderly controls. To see where in the brain and how strongly THK523 binds compared to PIB, each person got an injection for both tracers.

How did the tau ligand do? In a word, so-so. As desired, it enters the brain well and washes out quickly, and it shows no difference between AD and normal in the cerebellum, a control region for AD pathology. In cortical regions known to be laden with neurofibrillary pathology in AD, THK523 did have differential retention between AD and controls, but the signal was disappointingly small, Villemagne said.

“Visually, you cannot see much of a difference,” Villemagne said, and visual inspection is important for eventual success in the clinic. Using quantitative analysis, the researchers do find higher THK523 retention in AD than in semantic dementia and controls. Among the controls, the 85-year-old showed more retention in the hippocampus than did the 70-year-old, which fits the age-related increase in neurofibrillary tangles there, Villemagne said. Also encouraging was that PIB and THK523 had different regional patterns of retention, where the latter follows the pattern of FDG hypometabolism, which is believed to reflect neurodegeneration downstream of amyloid deposition. In toto, then, this compound is a start, Villemagne, said, but not good enough (Villemagne et al., 2012).

In discussion, other scientists were more upbeat. Some pointed out that the signal THK523 yields is about the same or slightly better than what is achievable with PK11195, a PET ligand for neuroinflammation. Others pointed out that it does have higher affinity for tau and better selectivity than does FDDNP, another tracer that finds occasional use (Harada et al., SfN 2011). “You call THK523 a failure,” said Chet Mathis, a co-developer of PIB, “but it is a failure only by the high standards of PIB.” In any event, THK523 is not the last word. A second-generation compound by the same Japanese group, called 18F CPDE, is nearing first human tests as well; it is going to be developed commercially, Villemagne said.

Yet another tau tracer entered the stage at HAI, when Kolb, a nuclear medicine chemist who formerly worked in cancer and hypoxia, introduced the preclinical agents 18F-T807 and 18F-T808. These came out of competitive compound screens run on human brain slices. Rather than using human tau expressed in transgenic mice, Kolb decided to search for compounds that bind native tau as it occurs in patients. The binding affinity of the two tau ligands are 15 and 22 nM, respectively—perhaps a tad low, according to other scientists at HAI. Tied to fluorescent probes, the two compounds visualize human neurofibrillary tangles, Kolb said, adding that they bind tau with a 29-fold selectivity over Aβ and have shown no significant off-target binding. The 18F compounds stained tau pathology in autoradiographs of slices of 37 human brains, corresponding well to tau immunofluorescence, Kolb said. The compounds penetrate the blood-brain barrier in mice and primates, wash out within half an hour, and have shown no toxicity, he added (Kolb et al., 2012). Siemens has filed an exploratory IND for both compounds in December 2011, and intends to begin human testing this spring, Kolb said. There are no published data on these compounds.—Gabrielle Strobel.

This is Part 9 of a nine-part series. See also Part 1, Part 2, Part 3, Part 4, Part 5, Part 6, Part 7, Part 8. Download a PDF of the entire series.


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News Citations

  1. Miami: Diagnosis and Amyloid Scan Can Be at Odds
  2. News Focus: 2012 Human Amyloid Imaging Conference
  3. Miami: Amyloid PET in the Clinic: What Are the Issues?
  4. Miami: Scan and Tell? Amyloid Imaging Confronts Disclosure Dilemma
  5. Miami: Can the Naked Eye Tell When a Scan Is Positive?
  6. Miami: When Does Amyloid Deposition Start in Familial Alzheimer’s?
  7. Miami: Age and Amyloid—What Has ApoE Got to Do With It?
  8. Miami: Longitudinal Amyloid PET Data Start Converging

Paper Citations

  1. . 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. Brain. 2011 Apr;134(Pt 4):1089-100. PubMed.
  2. . In Vivo Tau Imaging. Human Amyloid Imaging Abstract. 2012 Jan 1;
  3. . Discovery of Novel [18F]-PET Agents for Imaging Neurofibrillary Tangles (NFTs). Human Amyloid Imaging Abstract. 2012 Jan 1;

Other Citations

  1. Download a PDF of the entire series.

External Citations

  1. Harada et al., SfN 2011

Further Reading