23 May 2024

The hunt for PET tracers that can detect four-repeat tau deposits has turned up two ligands, PI-2620 and APN-1607, that bind these fibrils, but neither has yet been validated for diagnostic use. In a May 7 preprint on bioRxiv, researchers led by Matthias Brendel, Nicolai Franzmeier, Sigrun Roeber, and Günter Höglinger of Ludwig Maximilians University of Munich strengthen the case that Life Molecular Imaging’s PI-2620 detects 4R tau in living brains. This form of tau accumulates in tauopathies such as progressive supranuclear palsy and corticobasal degeneration. The authors report that in six PSP patients, the PET signal during life correlated with 4R tau deposits in their brains detected by autoradiography and immunostaining after death. The signal came from neurons and oligodendrocytes, but not astrocytes. The authors identified the gray/white-matter boundary in the frontal cortex as having the strongest PET signal, suggesting that focusing on this region could sharpen PI-2620’s ability to discriminate 4R tauopathies from healthy controls.

While calling the findings an advance, scientists remained agnostic about PI-2620’s diagnostic utility for 4R tauopathies. “This elegant study … shows a strong correlation of regional PI-2620 signals to abundance of fibrillary tau,” Neil Vasdev at the University of Toronto wrote to Alzforum. Rik Ossenkoppele at Vrije University Amsterdam agreed the study was well-done, but cautioned there remains substantial overlap between the PET signal in 4R tauopathy patients and controls. “I am not convinced yet that the in-vivo signal of this tracer is strong and robust enough for offering diagnostic and/or prognostic value at the individual level in suspected primary 4R tauopathies,” he wrote (comments below).

Besides PI-2620 and APN-1607, other 4R tau tracers are in development. Vasdev and colleagues Chet Mathis at the University of Pittsburgh and Samuel Svensson at biotech Oxiant Discovery in Södertälje, Sweden, have identified a candidate, OXD-2314.

Lit Up: 4R Tau. Correlation of the PET signal (bottom, red) in basal ganglia of six PSP patients with postmortem AT8 staining (top) and PI-2620 autoradiography (middle) of tissue from those regions. [Courtesy of Slemann et al., bioRxiv.]

Previously, Brendel and colleagues reported that PI-2620 lit up basal ganglia and frontal cortex in PSP patients, and bound to those sections in banked brain samples. The tracer distinguished typical PSP patients from controls with 85 percent sensitivity and 77 percent specificity, but the PET signal was weak (Jul 2020 news). Other studies reported mixed findings for whether the tracer recognized 4R tau in postmortem brain (Malarte et al., 2023; Aguero et al., 2024). 

To gather more comprehensive data, joint first authors Luna Slemann, Johannes Gnörich, Selina Hummel, and Laura Bartos first used ^18FPI-2620 to scan PS19 mice, which carry P301S mutant human tau and accumulate 4R aggregates starting at about 6 months of age. By 10 months, the PET signal in PS19 mice was distinguishable from that in control mice, being 20 percent higher. To find out what cell types contributed to the signal, the authors isolated neurons and astrocytes immediately after administering the PET tracer, and measured the radioactivity in each. All the signal came from neurons, with PS19 neurons having about twice as much tracer binding as those from wild-type mice.

Moving to people, Slemann and colleagues found that in the six PSP patients who had been scanned during life and donated their brains, the PET signal correlated with autoradiography of tissue isolated from their basal ganglia, and with tau aggregates as judged by AT8 staining. PET scans had been done an average of two years before death; tighter timing might have improved the radiography and tangle correlations of 0.89 and 0.82, respectively, the authors noted.

The authors zeroed in on specific cell types in human tissue, comparing AT8 staining with PI-2620 autoradiography in frontal cortex sections from 16 additional PSP brains. There were more tau deposits in astrocytes than in neurons and oligodendrocytes as per immunohistochemistry; even so, the PET signal came exclusively from the latter two. Likely this is because neuronal and oligodendrocyte deposits are denser, boosting the PET signal, Franzmeier told Alzforum. Astrocytes' many fine processes scatter their tau deposits over a broad area, rendering the PET signal too faint to see. Tangle-bearing “tufted” astrocytes are a hallmark of PSP.

In line with this cellular distribution, the authors found that the PET signal was strongest near the gray/white-matter boundary in the frontal cortex, probably because of the density of oligodendrocytes in this region. The signal there distinguished 17 PSP scans from nine control scans with a Cohen’s d effect size of 1.68, compared with 1.37 when using the gray-matter signal. Ideally, a diagnostic scan would combine PET with MRI to quantify the signal in the gray/white-matter boundary, Franzmeier said.

Makoto Higuchi at the National Institute of Radiological Sciences, Japan, noted that technical issues, such as radioactivity spillover from the extracranial space, still dog PI-2620 imaging. These would need to be addressed before assessing the tracer’s reliability, he wrote. Higuchi also wanted to know how the gray/white-matter boundary performs diagnostically for discriminating PSP cases and controls (comment below). Franzmeier said they are now assessing the clinical utility of PI-2620 visual reads.

Meanwhile, Vasdev, Mathis, and Svensson previously developed a PET tracer, OXD-2115, with high affinity for 4R tau (Lindberg et al., 2021). Because that tracer poorly entered brain, they developed analogs with better uptake. Their current lead candidate, OXD-2314, performed well in rats and non-human primates, and will now start human trials, Vasdev told Alzforum.—Madolyn Bowman Rogers

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. At Holloway Summit, FTD Imaging Shows New Vista 19 Dec 2023
2. PET Tracer PI-2620 Detects 4R Tau Deposits 10 Jul 2020

Research Models Citations

1. Tau P301S (Line PS19)

Paper Citations

1. Malarte ML, Gillberg PG, Kumar A, Bogdanovic N, Lemoine L, Nordberg A. Discriminative binding of tau PET tracers PI2620, MK6240 and RO948 in Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy brains. Mol Psychiatry. 2023 Mar;28(3):1272-1283. Epub 2022 Nov 29 PubMed. Correction.
2. Aguero C, Dhaynaut M, Amaral AC, Moon SH, Neelamegam R, Scapellato M, Carazo-Casas C, Kumar S, El Fakhri G, Johnson K, Frosch MP, Normandin MD, Gómez-Isla T. Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases. Acta Neuropathol. 2024 Jan 27;147(1):25. PubMed.
3. Lindberg A, Knight AC, Sohn D, Rakos L, Tong J, Radelet A, Mason NS, Stehouwer JS, Lopresti BJ, Klunk WE, Sandell J, Sandberg A, Hammarström P, Svensson S, Mathis CA, Vasdev N. Radiosynthesis, In Vitro and In Vivo Evaluation of [18F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies. ACS Chem Neurosci. 2021 Feb 17;12(4):596-602. Epub 2021 Jan 26 PubMed.

Further Reading

News

1. At Holloway Summit, FTD Imaging Shows New Vista 19 Dec 2023
2. Primary Tauopathies Get New PET Ligands 6 Mar 2020
3. Tau PET: The Field Expands Rapidly 26 Feb 2020