Lindberg A, Murrell E, Tong J, Mason NS, Sohn D, Sandell J, Ström P, Stehouwer JS, Lopresti BJ, Viklund J, Svensson S, Mathis CA, Vasdev N. Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies. Nat Commun. 2024 Jun 14;15(1):5109. PubMed.
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National Institute of Radiological Sciences
Mathis, Vasdev, and colleagues provide a model protocol for designing and evaluating PET radioligands based on chemical, pharmacokinetic, and pharmacodynamic properties. The validity of this approach will soon be examined by a clinical PET study for AD and non-AD tauopathy cases. The new tracer, 18F-OXD-2314, has a relatively long backbone structure (indol-pyridine-piperidin BBQ) similar to 18F-florzolotau, and presumably these compounds bind to hydrophobic grooves spanning stacked β-strands of tau molecules (Shi et al., 2021). As these groove-shaped binding pockets are present across the cross-beta motif of diverse tau fibril folds, such “long” chemicals are potentially reactive with a wide range of tau pathologies.
The notable difference between OXD-2314 and florzolotau is that the former contains a pyridine ring instead of a butadiene linker to circumvent photoisomerization issues. I sense that the florzolotau backbone, including the slender linker portion in the middle, may show a lock-and-key fit to the wavy surface of the groove, but this view needs to be tested by in-depth molecular docking.
Among various assessments in the current study, homogenate binding assays to determine the affinity of the compounds have illustrated the most intriguing features, as the dissociation constants (KDs) of OXD-2314 in PSP, CBD, and PiD were considerably lower than those of florzolotau. A slightly complicated issue is that the homologous blockade curves for OXD-2314 were well described by a two-site binding model, and KDs of this compound for the high-affinity binding site were compared to KDs of florzolotau.
There is no information on whether a one- or two-binding model was employed for the fit to the florzolotau binding curves to determine KDs. It is also unclear whether the low-affinity, high-capacity binding of OXD-2314, which accounts for 20 percent to 30 percent of the total binding, reflects tau or non-tau pathologies. Another interesting point is the lack of displacement of 3H-OXD-2314 binding with florzolotau, contrary to the notion that both ligands could be docked with the grooves in the cross-beta spine of tau fibrils. The Bmax/KD values of OXD-2314 were also very high in a three-digit range and should be compared with those of florzolotau.
Moreover, the Bmax/KD values of OXD-2314 were 550 in the AD cortex, 580 in the PSP cortex, and 1,000 in the PSP subcortex, indicating greater binding of this compound in PSP than in AD. This might not be consistent with autoradiographic findings since intense labeling was noted in AD rather than PSP slices. The Bmax/KD values of OXD-2314 were 371 in the CBD frontal cortex, while very strong displaceable binding was homogeneously observed in the autoradiography of a CBD frontal cortical sample.
The rodent and monkey PET data revealed ideal pharmacokinetic and metabolic profiles of 18F-OXD-2314. This ligand was also shown to react with tau aggregates in transgenic mice, and it would be nice to demonstrate the in vivo labeling of tau deposits in rTg4510 mice with 18F-OXD-2314, which could be compared to the florzolotau data in the literature (Kimura et al., 2022). For the advancement of diagnostic technologies, it will be crucial to carry out comparative tests of different tau PET probes with proper methodologies in non-clinical and clinical settings.
References:
Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SH, Goedert M. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. 2021 May;141(5):697-708. Epub 2021 Mar 16 PubMed. Correction.
Kimura T, Ono M, Seki C, Sampei K, Shimojo M, Kawamura K, Zhang MR, Sahara N, Takado Y, Higuchi M. A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model. Eur J Nucl Med Mol Imaging. 2022 Nov;49(13):4298-4311. Epub 2022 Jul 8 PubMed.
View all comments by Makoto HiguchiLudwig Maximilian University Hospital
The development of [18F]OXD-2314 heralds a promising advance in the imaging of tauopathies, particularly the non-Alzheimer's disease (non-AD) type. This new tracer, designed through a ligand-based approach, shows high affinity and selectivity for 4R-tau aggregates, characteristic of diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). While [18F]OXD-2314 has shown promising preclinical results with higher binding affinity in PSP and CBD tissues and favorable pharmacokinetic properties, it has not yet been tested in human subjects.
Therefore, it will be important to compare it clinically with [18F]PI-2620 and [18F]PM-PBB3, aka APN-1607, which have been established as reliable tracers for imaging tau pathology in both AD and non-AD tauopathies. [18F]PI-2620 and [18F]PM-PBB3 have been evaluated in patients and have shown the ability to image tau aggregates effectively in conditions such as PSP and corticobasal syndrome (CBS) (Brendel et al., 2020; Palleis et al., 2021; Tagai et al., 2021). In addition, a small number of patients who have been imaged with [18F]PI-2620 and undergone autopsy upon death, corroborated the binding of the tracer to regions of the brain with 4R tau accumulation (Selmann et al., 2024).
The next steps for [18F]OXD-2314 involve crucial, human PET studies to validate its preclinical potential. If [18F]OXD-2314 can match or exceed the performance of [18F]PI-2620 or [18F]PM-PBB3 in clinical trials, it may become a valuable addition to the tool kit for imaging tau pathology. That [18F]OXD-2314 appears to have a unique binding site different than existing tau radiotracers is quite interesting. This may provide a different imaging profile, with respect to both on target and off target binding.
The success of [18F]OXD-2314 in upcoming human studies will be eagerly anticipated, potentially enhancing the landscape of tau imaging in neurodegenerative diseases.
References:
Brendel M, Barthel H, van Eimeren T, Marek K, Beyer L, Song M, Palleis C, Gehmeyr M, Fietzek U, Respondek G, Sauerbeck J, Nitschmann A, Zach C, Hammes J, Barbe MT, Onur O, Jessen F, Saur D, Schroeter ML, Rumpf JJ, Rullmann M, Schildan A, Patt M, Neumaier B, Barret O, Madonia J, Russell DS, Stephens A, Roeber S, Herms J, Bötzel K, Classen J, Bartenstein P, Villemagne V, Levin J, Höglinger GU, Drzezga A, Seibyl J, Sabri O. Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy. JAMA Neurol. 2020 Nov 1;77(11):1408-1419. PubMed.
Palleis C, Sauerbeck J, Beyer L, Harris S, Schmitt J, Morenas-Rodriguez E, Finze A, Nitschmann A, Ruch-Rubinstein F, Eckenweber F, Biechele G, Blume T, Shi Y, Weidinger E, Prix C, Bötzel K, Danek A, Rauchmann BS, Stöcklein S, Lindner S, Unterrainer M, Albert NL, Wetzel C, Rupprecht R, Rominger A, Bartenstein P, Herms J, Perneczky R, Haass C, Levin J, Höglinger GU, Brendel M. In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies. Mov Disord. 2021 Apr;36(4):883-894. Epub 2020 Nov 27 PubMed.
Palleis C, Sauerbeck J, Beyer L, Harris S, Schmitt J, Morenas-Rodriguez E, Finze A, Nitschmann A, Ruch-Rubinstein F, Eckenweber F, Biechele G, Blume T, Shi Y, Weidinger E, Prix C, Bötzel K, Danek A, Rauchmann BS, Stöcklein S, Lindner S, Unterrainer M, Albert NL, Wetzel C, Rupprecht R, Rominger A, Bartenstein P, Herms J, Perneczky R, Haass C, Levin J, Höglinger GU, Brendel M. In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies. Mov Disord. 2021 Apr;36(4):883-894. Epub 2020 Nov 27 PubMed.
Slemann L, Gnorich J, Hummel S, Bartos LM, Klaus C, Kling A, Kusche-Palenga J, Kunte ST, Kunze LH, Englert AL, Li Y, Vogler L, Katzdobler S, Palleis C, Bernhardt A, Jäck A, Zwergal A, Hopfner F, Romer S, Biechele G, Stocklein S, Bischof G, vanEimeren T, Drzezga A, Sabri O, Barthel H, Respondek G, Grimmer T, Levin J, Herms J, Paeger L, Willroider M, Beyer L, Hoglinger GU, Roeber S, Franzmeier N, Brendel M. Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies. 2024 May 07 10.1101/2024.05.04.592508 (version 1) bioRxiv.
View all comments by Matthias BrendelBoston University CTE Center
Lindberg et al. provide compelling evidence for OXD-2314 as a new lead candidate for imaging non-AD tauopathies, and AD. Indeed, 3HOXD-2314 had selective and stronger binding affinity for tau aggregates of PSP and CBD in postmortem tissue compared with other tritium-labeled PET ligands, PI-2620, florzolotau, OXD-2115. The authors also provided evidence that OXD-2314 penetrates brain. To date, tau PET radiotracers have been optimized for the detection of the 3R/4R tau aggregates related to AD.
Research has been studying tracers that work for AD to determine their usefulness in non-AD tauopathies, but I don’t think that this is the best approach. For example, currently available radiotracers (e.g. TAUVID) show low-intensity, variable binding with small effects in humans with CTE tau aggregates. While CTE is a 3R/4R tauopathy and was not examined here, existing data suggest that tau might be predominantly 4R in the early stages and therefore [18F]OXD-2314 could be a potential game-changer for the in-vivo detection of CTE tau. The same could be true for PSP and CBD.
There needs to be discovery efforts, like those of Lindberg et al., that develop and optimize tau radiotracers for non-AD tauopathies instead of relying on what works for AD. Overall, this is an important development for the AD/ADRD field, and in vivo data from human trials will be much anticipated.
View all comments by Michael AloscoLund University
Since the development of tau PET tracers capable of detecting the 3R/4R tau pathology in Alzheimer’s disease, there have been increased efforts to find new tracers that specifically detect 4R tau in PSP and CBD.
This work by Lindberg et al. from the Vasdev lab represents a significant contribution to the field with the addition a novel chemical group of tau PET tracer compounds. The preclinical evaluation and characterization of these compounds are thorough. The lead compound, OXD-2314, demonstrates good selectivity for tau over Aβ and α-synuclein, with no obvious off-target binding in vitro.
However, OXD-2314 faces similar challenges regarding specificity for 4R tau versus mixed 3R/4R tau and 3R tau, as seen with previous 4R-tau PET compounds (PI-2620 and florzolotau). Nonetheless, OXD-2314 appears to have a slightly higher affinity for 4R tau, particularly in the case of CBD-related tau. A key difference between these tracers is that OXD-2314 seems to bind to a distinct site on tau aggregates compared to PI-2620, florzolotau, tauvid, and MK-6240, as its binding cannot be blocked by these compounds in competition experiments. Potentially this could explain the increase in affinity.
Although the ideal 4R tau tracer should be specific and preferably not bind to mixed 3R/4R or 3R tau, an increase in affinity that allows for the detection of cortical and subcortical 4R tau would still be a significant advancement. Differences in cortical and subcortical binding patterns could still help differentiate the various tau-related neurodegenerative disorders from one another. In vivo, OXD-2314 shows rapid brain uptake and washout in rodent and non-human primate models, along with low non-specific binding in these models, which is promising.
Overall, this novel PET tracer class is a valuable addition to the array of tau PET tracers and shows promise in preclinical testing. The critical question now is whether the tracer will perform as well in vivo in humans. I look forward to seeing the results from these scans.
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