The current crop of tau PET tracers have yielded new insights into the progression of Alzheimer’s disease, but they are plagued by problems. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29 to April 2 in Austria’s capital, Vienna, researchers debuted new tracers that appear at first glance to be able to overcome the limitations of the earlier compounds. In general, the newcomers boast higher brain uptake and more specific binding, yielding cleaner-looking scans with sharper distinction between positive and negative findings. While the older tracers work only in AD, some of the new ones appear to light up other tauopathies, as well. Researchers at Piramal Imaging wowed the crowd with scans showing a distinct, specific pattern of binding of their tracer in progressive supranuclear palsy (PSP) compared to AD. Earlier this year, researchers from Merck reported on their tau PET tracer, MK-6240, at the Human Amyloid Imaging (HAI) meeting held January 11-13 in Miami Beach, Florida. Like Piramal’s, Merck’s tracer is being readied for broad distribution. Researchers from Genentech and Roche reported longitudinal data for their in-house tracers in Phase 1 tests, while Janssen scientists at AD/PD showed massive brain uptake of their candidate in preclinical studies.

All five new tracers are at an early stage of development, but even as they undergo validation, clinicians across the field are urgently casting about for tau PET tracers to use in their observational and drug studies. They are in a pinch because the most validated tracer thus far, Lilly/Avid’s AV-1451 (aka T807, flortaucipir), is either unavailable or unaffordable for most groups. Another hopeful fizzled out thanks to off-target binding in key regions, and some of the new tracers are being developed by drug companies for internal and academic use. This situation leaves clinicians scrambling for a ligand to image tau pathology in their participants, with many now eyeing Merck’s and Piramal’s.

Researchers at AD/PD applauded the advent of more options. They called the preliminary data from the new batch promising, while cautioning that data from larger cohorts and in additional tauopathies are needed to verify how well these work in practice. “I am excited to see so many companies developing tau tracers. I hope to use one of these to develop new anti-tau treatments,” Philip Scheltens of VU University Medical Center, Amsterdam, wrote to Alzforum. At HAI, Bill Jagust of the University of California, Berkeley, quipped, “My favorite tracer is always the one I have not yet seen,” alluding to PET experts’ general experience that new tracers tend to start out looking great, until more scans in more people turn up their limitations. 

Distinct Diseases. Piramal’s PI-2620 tracer has different uptake patterns in AD (top) and PSP (bottom). [Courtesy of Andrew Stephens.]

First Generation Tracers: A Mixed Track Record
Though imperfect, tau PET has already begun to transform the field. Studies to date, done mostly with AV-1451, have found that tau ligand binding matches Braak staging, advances with disease stage, and correlates with cognitive deficits (see Aug 2016 conference newsAug 2016 news). Researchers are especially excited by emerging data hinting that tau tracer uptake increases rapidly as disease progresses, well within the detection time of a clinical trial, and that it appears to track cognitive decline early on in disease. 

At the same time, researchers note problems, such as off-target binding in the choroid plexus and striatum, and low sensitivity for distinguishing AD cases from healthy controls, that stem from a relatively small dynamic range (see Feb 2016 conference news; Feb 2016 conference news). While AV-1451 binds to the paired helical fragments found in AD and in certain tau mutations causing frontotemporal dementia (FTD), this tracer does not recognize the three-repeat (3R) and four-repeat (4R) tau isoforms that predominate in tauopathies such as Pick’s disease, PSP, corticobasal degeneration (CBD), and most cases of frontotemporal dementia (see Sep 2016 conference news). AV-1451 also binds only weakly to tau in chronic traumatic encephalopathy (CTE).

Another existing tau tracer has been felled by nonspecific binding. This is THK5351, discovered at Tohoku University in Sendai, Japan, and licensed by GE Healthcare for commercial distribution. At this year’s HAI meeting, three groups reported THK5351 binding to the enzyme MAO-B, possibly on astrocytes. This clouds interpretation of the scans. Tohoku’s Ryuichi Harada reported that THK5351 bound to recombinant MAO-B in vitro and was displaced by an MAO-B inhibitor in basal ganglia of a human control. Qi Guo from AbbVie in Chicago showed that MAO-B accounted for up to 70 percent of the THK5351 signal in competitive binding and displacement studies in cynomolgus monkeys and homogenate of human AD entorhinal cortex. And in Pedro Rosa-Neto’s lab at McGill University in Montreal, the MAO-B inhibitor selegiline wiped out up to half of the prior THK5351 signal in four study participants with mild cognitive impairment or PSP.

“THK5351 has so much off-target binding that its value as a tau tracer is compromised,” Keith Johnson of Massachusetts General Hospital said at HAI. Other PET experts put it more bluntly: “Substantial off-target binding in a target region is the kiss of death,” said Chet Mathis of the University of Pittsburgh School of Medicine. Adding to the tracer’s woes, researchers at Janssen Pharmaceutica, Beerse, Belgium, reported on a poster at AD/PD that, in their hands, THK5351 also bound to aggregated Aβ in AD brain slices. Clinical researchers across the field who had been planning to use THK5351 held their horses once its MAO-B binding became apparent, and are seeking an alternative.

Goodbye GE, Hello … Piramal? Merck?
In Vienna, Andrew Stephens at Piramal Imaging, Berlin, Germany, described his group’s search for tau ligands. In collaboration with AC Immune, Lausanne, Switzerland, they screened compounds for binding to AD brain homogenate or to synthetic tau paired helical fragments. Their lead, PI-2620, bound to brain regions with high tau tangles but gave no signal from non-demented control brains. Neither did it bind Aβ fibrils. PI-2620 had but low affinity for MAO-B, or to MAO-A for that matter, the related enzyme that had temporarily mired the tracer AV-1451 in controversy until researchers agreed that AV-1451’s MAO-A binding in humans was of too low affinity to interfere with measuring tau. Importantly, PI-2620 bound strongly to 3R tau from Pick’s and 4R tau from PSP brains, Stephens said. The tracer also demonstrated suitable pharmacokinetic properties. In wild-type mice and nonhuman primates, it entered the brain well and washed out within an hour. PI-2620 is Piramal’s second tau tracer, replacing a weaker candidate called MNI-815.

Based on these findings, Piramal started a Phase 1 trial on four people with AD, three with PSP, and two healthy controls. It was run by John Seibyl of Molecular NeuroImaging, an imaging services company in New Haven, Connecticut, with PI-2620 receiving the designation MNI-960 for clinical testing. As in animal studies, the researchers saw robust brain uptake, fast washout, and little signal in the pertinent brain regions of controls. The signal plateaued 60 to 90 minutes after tracer injection, Seibyl noted in Vienna. Typical SUVRs for AD patients ran from 2.5 to 2.8.

Notably, AD and PSP scans revealed distinct patterns (see image above). In PSP, only a few discrete regions, mainly the pallidum and substantia nigra, lit up. In contrast, AD patients took up tracer in broader areas known to accumulate tau tangles, such as the lateral temporal lobe, hippocampus, entorhinal cortex, and precuneus.

Curiously, one of the AD patients had a negative tau scan. Stephens noted this patient had mild AD, with an MMSE of 26, and may not have accumulated much pathological tau yet. Incidentally, other PET experts, too, noted that as more research groups image both amyloid and tau pathology in the same cognitively impaired people, they are finding a few whose scans are amyloid-positive but tau-negative.

Importantly, the researchers saw no uptake of PI-2620 in choroid plexus, amygdala, or striatum, where other tracers have off-target binding. In particular, choroid plexus uptake can be nettlesome because this structure sits atop the hippocampus, hence uptake there could bleed into this important region and confound tau measurement. Overall, AD patients looked markedly different from controls in temporal regions, suggesting the tracer discriminates well between cases and controls, Stephens added.

Liana Apostolova of Indiana University, Indianapolis, noted that the absence of nonspecific binding in choroid plexus represents a significant advantage of this tracer over others. She was also impressed by the solid cortical binding in AD and specificity of the binding in PSP. “So far, PI-2620 is looking very good,” she wrote to Alzforum. Victor Villemagne of the University of Melbourne, Australia, who chaired the AD/PD session, said, “[PI-2620] truly represents a second generation of tracers.”

The data also raised questions. Some patients displayed an asymmetric pattern with more uptake on one side of the brain. “The heterogeneity of the tau distribution and load in patients who are β-amyloid positive is perhaps unexpected,” Stephens wrote to Alzforum. More research is needed to determine how this variable regional and temporal tangle accumulation relates to cognitive decline and amyloid, he noted.

At AD/PD, audience members observed that PI-2620 appears to bind to the eyes and to bone at the margins of the skull. Stephens said the eye signal might represent binding to melanin or other pigments. He speculated that tracer accumulating around the skull is not detecting bone or meninges, but might reflect a PI-2620 metabolite in blood that cannot enter brain. A meningeal signal is unwelcome if it is large enough to spill into the top of the cortex, a region of interest.

A healthy elderly volunteer (top) whose amyloid scan was negative showed low, homogeneous MK-6240 uptake across the brain, without a signal in hippocampus or medial temporal lobe. An older AD patient whose amyloid scan was positive showed high MK-6240 uptake in known tau pathology regions such as the medial temporal lobe and inferior temporal cortex. [Courtesy Jeffrey Evelhoch.]

Merck: Alternative for Wide Distribution?
If Piramal’s tracer holds up in further study, it would be sold to any drug developer or clinician, but it has competition. The pharma giant Merck has developed a tau tracer, called MK-6240, which has completed one Phase 1 trial and is recruiting for another. At HAI last January, Cyrille Sur, Jeffrey Evelhoch, and colleagues at Merck in West Point, Pennsylvania, presented data on the first use of 18F MK-6240 in people. By that point, Merck had studied the compound in about 10 middle-aged adult controls and 10 people with AD. They worked with researchers in Leuven, Belgium, and at the Boston-based imaging CRO InviCRO, in collaboration with Biogen, which has licensed this tracer for use in its aducanumab and other Biogen trials. 

MK-6240 showed uptake in the brain regions consistent with Braak stage, including the parahippocampus, medial temporal cortex, and amygdala. Comparing the new tracer primarily to the standard bearer AV-1451, Cyr said that MK-6240 has a wider dynamic range. In addition, its higher affinity for neurofibrillary tangles means it requires lower doses, making it easier to run baseline and follow-up scans within a year, Cyr said. In Europe especially, radiation exposure laws can limit the repeat PET scans required for longitudinal studies or clinical trials.

Cyr further reported that in monkey studies and the initial human trial, MK-6240 showed none of the off-target binding in the choroid plexus and striatum seen with AV-1451, though other PET experts cautioned that additional research in older controls might yet turn up such binding. Thus far, the only overt off-target binding appears to be in a left leptomeningeal region, which could get in the way if it bleeds into the cortex there. Researchers who saw MK-6240 data at last year’s AAIC were cautiously optimistic (Aug 2016 conference news). 

Both the preclinical characterization of this compound, as well as information on how it can be synthesized for widespread research use, are formally published (Hostetler et al., 2016Collier et al., 2017). 

Tracking Progression.

Genentech's GTP1 tau tracer reveals an increase in tau accumulation in a person with mild AD (right column) over six months. [Courtesy of Sandra Sanabria Bohorquez.]

Importantly for the field, Merck wants MK-6240 to become broadly available. “We want our tracer to get out there for the community to use in therapeutic trials,” Evelhoch told Alzforum. Merck routinely develops PET tracers for target engagement of its investigational drugs, but as a pharma company does not take on their scale-up, setup of distribution centers, and commercialization. Therefore, Merck in January 2017 licensed clinical development and sale of MK-6240 to Cerveau Technologies, a partnership between the Toronto-based company Enigma Biomedical Group and the Beijing-based Sinotau Pharmaceutical Group. In the months since, Cerveau has signed a manufacturing agreement with Siemens’ PETNET, and research and validation agreements with Rosa-Neta at McGill, Sterling Johnson at the Wisconsin Alzheimer’s Disease Research Center, Chris Rowe at Austin Health in Melbourne, with Biogen, and with Sinotau for development in China. Johnson told Alzforum that he was going to use THK5351 but switched to a combination of AV1451 and MK-6240 after the HAI meeting.

Genentech, Roche, Janssen: New In-House Tracers
Brain imaging researchers agree that the trouble obtaining AV1451 has spurred a welcome burst of international effort to come up with alternatives, and recent conferences featured updates on three more such programs. Researchers at Genentech, South San Francisco, are taking their next-generation tau tracer GTP1 through an 18-month longitudinal Phase 1 study. Last summer, Genentech’s Sandra Sanabria Bohorquez reported that the tracer signal intensified in the temporal lobes and hippocampi of AD patients over six to nine months, suggesting it is sensitive to small changes in tau load (see Aug 2016 conference news). At the time, the cohort consisted of six controls, six people with prodromal AD, and 10 mild to moderate AD patients. Adding new data, Sanabria Bohorquez in Vienna reported on 14 controls, 13 people with prodromal, and 25 with mild to moderate AD. The tracer signal matched the expected distribution of tau tangles at increasing Braak stages, and well distinguished cases from controls, and prodromal from mild to moderate, she reported. In general, people who have a higher amyloid plaque load also retain more GTP1.

As before, the GTP1 signal picked up changes over six to nine months in people with AD. This is important because it hints that GTP1 might track progression and possibly treatment response within the timeframe of a Phase 2 trial. At HAI, Sanabria reported that this tracer does not bind MAO-A or B. Similar to AV1451, in some subjects GTP1 does generate a signal in the basal ganglia that may be due to age-related changes other than tau. Genentech is building distribution centers to start using GTP-1 in therapeutic trials, including the crenezumab trials in sporadic disease (CREAD1 and 2) and Paisa mutation carriers in Colombia. Sanabria said Genentech will share its tracer with academic investigators, but currently has no plans to distribute it commercially on a larger scale.

At HAI, Mike Honer, Edilio Borroni, and colleagues at Roche presented the latest on their company’s tau tracer. RO6958948 is structurally similar to T807 (AV1451/flortaucipir), and it behaves similarly, too. In vitro binding studies on fresh-frozen tissue sections from people who had died with AD or a range of other tauopathies showed that RO6958948 binds tau aggregates in AD and in select tau mutation cases, as does AV1451. RO6958948 does not bind robustly in tissue from people who had Pick’s disease, PSP, or CBD. Also at HAI, Dean Wong of Johns Hopkins University in Baltimore, who collaborates with Roche in evaluating this tracer clinically, reported on the first four AD cases from a Phase 1 follow-up study of RO6958948. For all four people, MMSE score worsened between their baseline and follow-up scans some eight to 22 months later; for three of those four, tau PET SUVR values nudged up, as well. This trial is ongoing.

Borroni told Alzforum that Roche plans to use this tracer to help evaluate its investigational AD treatments, and would make it available to academic investigators and to international initiatives such as EPAD (see Aug 2015 conference news). 

Last but not least, Janssen is getting into the action with a ligand that appears headed to Phase 1. In Vienna, Diederik Moechars showed that his team searched for new tau ligands by screening compounds for their ability to out-compete the original ones, T808 and T807. Janssen’s lead candidate, JNJ-067, bound tau tangles extracted from Braak stage 5 and 6 AD brains more strongly, and was more selective for tau over Aβ fibrils. It detected tau in AD brain slices. JNJ-067 had no affinity for MAO-A and low affinity for MAO-B, with binding starting only at concentrations of 1 μm or higher. It entered the brain readily and washed out quickly in a rhesus monkey. Notably, in this primate brain, uptake of JNJ-067 dwarfed uptake of T807, with a five times higher peak, while still washing out faster. If these properties hold up in humans, they could eventually shorten needed scan times with JNJ-067 compared to current tracers. Janssen is planning to take JNJ-067 into phase 1 this year but has not yet decided how to make it available, Moechars told Alzforum.

For the time being, however, Villemagne cautioned that other tau tracers have shown marked discrepancies between their preclinical profile and imaging in people. “Given this, it would be prudent to wait for the first human studies to see how it performs,” he wrote to Alzforum.—Madolyn Bowman Rogers and Gabrielle Strobel

Comments

  1. We (APRINOIA Therapeutics) presented clinical data on our new tau PET imaging tracer, 18F-PM-PBB3, at AD/PD 2017. We are developing new tau tracers, evolved from the first-generation 11C-PBB3 tracer invented at QST(NIRS) in Chiba, Japan (Maruyama et al., 2013). APRINOIA currently has two clinical tau PET tracer candidates and lead molecules for imaging α-synuclein pathology.

    Our initial clinical study of 18F-PM-PBB3 has shown limited off-target signal in basal ganglia, thalamus, and midbrain structures in healthy and MCI subjects, reflecting our in-vitro evidence that MAO-B or MAO-A does not contribute to PM-PBB3 binding to AD brain samples. However, in our first PSP patient scan, we did see elevated signals in those subcortical areas, indicating potential utility for both AD and non-AD tauopathies.

    In our study, we also observed 18F-PM-PBB3 retention in choroid plexus in some, but not all, AD and healthy subjects. We are currently expanding our studies in multiple countries to explore this phenomenon further. Given that the signal is not universal in all subjects, it might be of some physiological or pathological relevance.

    [Courtesy of Ming-Kuei Jang.]

    References:

    . Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013 Sep 18;79(6):1094-108. PubMed.

  2. We are in an exciting period, with new data regarding both old and new PET tau tracers.

    The picture, however, is probably very complex. It is quite possible that a single PET tau tracer will be insufficient to capture human tauopathies, because tau exists in many different forms and shows much greater complexity than do fibrillar amyloid plaques.

    We just published an article in Scientific Reports in which we compare the distinct cortical laminar distribution of tau to that of astrocytes in three Alzheimer brains (Lemoine et al., 2017). In this study, tritiated THK5117 showed a distinct laminar cortical binding similar to autoradiography with the MAO-B ligand 3H-deprenyl. Both showed extensive binding in the superficial and deep layers of the temporal neocortices, whereas the middle frontal gyrus showed even binding throughout the layers. 

    No, or only minor, competition was observed in the hippocampal region between 3H-THK5117 and unlabeled deprenyl, as well as between 3H-deprenyl and unlabeled THK5117 in the nanomolar concentration range that we use for autoradiography. This finding is critically important as, for the first time, it shows that at those concentrations, the tau tracer THK5117 does not bind MAO-B. These are concentrations you would expect in PET imaging.

    The close resemblance between our quantified 3H-THK5117 and 3H-deprenyl laminar profiles to our mind indicates a laminar association between tau deposits and activated astrocytes.

  3. The apparent loss of THK-5351 has been a problem for many research groups, including ours. It appears that the tracer target specificity for the initial generation of PET tau tracers was not adequately understood. Today we know about widespread MAO-B binding of THK-5351 that could impact interpretation, and some MAO-A binding of AV1451—what will we learn tomorrow about the other TAU tracers?

    All second-generation tau tracers appear to show varying degrees of non-specific uptake. While non -specific binding does not necessarily invalidate a tracer, the tau radiopharmacology field is now acutely aware of the need to fully characterize pet tracers so we do not continue to be ahead of ourselves.

    There is another point to be made. Some tracers, including tau tracers, because of their limited brain uptake as compared with FDG or amyloid tracers, or absent non-specific binding in key measurement regions, have the potential for dual use as clearance tracers. In de Leon et al., 2017, we show how THK5117 can be used to examine the clearance of CSF from the brain. This study afforded the following new observations:

    • There is CSF egress via olfactory nerve to nasal turbinates. First demonstration in living humans.
    • Ventricular CSF clearance is reduced in Alzheimer’s. 
    • There is high correlation between reduced ventricular CSF clearance (as per tau tracer) and brain Aβ deposition (as per amyloid tracer) in AD.
    • The strong correlation of ventricular clearance measures across radiotracers in the same subject suggests measurement of an individual trait.​

    References:

    . Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J Nucl Med. 2017 Sep;58(9):1471-1476. Epub 2017 Mar 16 PubMed.

  4. While it is exciting that next-generation tau PET tracers are entering human studies, caution is required before drawing strong conclusions about their strengths and weaknesses. The "off-target" signal detected in basal ganglia with AV1451, and most other first-generation tau tracers, is clearly age-related. If one were to study relatively young control subjects with AV1451, one would falsely conclude that the tracer shows little "off-target" binding, a conclusion that would be quickly debunked once individuals in their 70s and 80s are imaged. In fact, much of the early work suggesting low "off-target" binding with some of the new tracers suffers from this limitation.

    Similarly, as we learned with THK-5351, early data showing binding in individual patients with PSP or CBD can lead us to jump to the conclusion that we have a good biomarker for these pathologies, a conclusion that may prove to be premature as we accumulate more data and learn about tracer behavior.

    Finally, claims that AV1451 binding is highly specific for PHF-tau in AD are based primarily on autoradiography studies. Incidentally, these fail to predict the low affinity "off-target" signal seen in vivo, and fly in the face of clearly elevated in vivo signal reported by multiple groups in non-AD tauopathies, and also in patients with expected non-tau pathology (FTLD-TDP in GRN/C9 mutation carriers and svPPA patients, a patient with pathology-proven PD without tau presented at HAI by the MGH group).

    We have to be humble about the limitations of our knowledge about these tracers, and avoid making overarching claims that are supported by little data.

    To quote the last sentence from many papers (and the first in many grants): More research is needed!

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References

News Citations

  1. Tau PET Studies Agree—Tangles Follow Amyloid, Precede Atrophy
  2. Brain Imaging Suggests Aβ Unleashes the Deadly Side of Tau
  3. At HAI, Researchers Explore Diagnostic Potential of a Tau Tracer
  4. Shaky Specificity of Tau PET Ligands Stokes Debate at HAI
  5. Fluid NfL Shines, Tau PET Dims, in the Hunt for FTD Biomarkers
  6. Improving Tau PET: In Search of Sharper Signals
  7. New Imaging Data Tells Story of Travelling Tau

Therapeutics Citations

  1. Aducanumab

Paper Citations

  1. . Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles. J Nucl Med. 2016 Oct;57(10):1599-1606. Epub 2016 May 26 PubMed.
  2. . cGMP production of the radiopharmaceutical [(18) F]MK-6240 for PET imaging of human neurofibrillary tangles. J Labelled Comp Radiopharm. 2017 May 15;60(5):263-269. Epub 2017 Mar 23 PubMed.

External Citations

  1. Phase 1 trial 
  2. another
  3. Phase 1 study
  4. trial 

Further Reading