<i>In Silico</i> Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers

Graham, Thomas J. A.; Lindberg, Anton; Tong, Junchao; Stehouwer, Jeffrey S.; Vasdev, Neil; Mach, Robert H.; Mathis, Chester A.

doi:10.1021/acs.jmedchem.3c00775

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…The binding of PMPBB3 and PBB3 shows three and two highly strong binding sites (<−20.0 kcal/mol) on the FESs, respectively. None of these sites overlaps with the strongest binding site identified for CBD2115 (I 360 [T 361 ]H 362 ), which clearly reveals the distinct binding preferences of PMPBB3 and CBD2115 and may support the results from a current displacement study by Graham et al . Our previous metadynamics simulations for CBD and AD tau protofibrils also indicated very high binding for PMPBB3 .…”

Section: Resultssupporting

confidence: 86%

Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

Li,

Kumar,

Långström

et al. 2023

ACS Chem. Neurosci.

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Primary supranuclear palsy (PSP) is a rare neurodegenerative disease that perturbs body movement, eye movement, and walking balance. Similar to Alzheimer's disease (AD), the abnormal aggregation of tau fibrils in the central neuronal and glial cells is a major hallmark of PSP disease. In this study, we use multiple approaches, including docking, molecular dynamics, and metadynamics simulations, to investigate the binding mechanism of 10 first-and second-generations of PET tracers for PSP tau and compare their binding in cortical basal degeneration (CBD) and AD tauopathies. Structure−activity relationships, binding preferences, the nature of ligand binding in terms of basic intermolecular interactions, the role of polar/charged residues, induced-fit mechanisms, grove closures, and folding patterns for the binding of these tracers in PSP, CBD, and AD tau fibrils are evaluated and discussed in detail in order to build a holistic picture of what is essential for the binding and also to rank the potency of the different tracers. For example, we found that the same tracer shows different binding preferences for the surface sites of tau fibrils that are intrinsically distinct in the folding patterns. Results from the metadynamics simulations predict that PMPBB3 and PBB3 exhibit the strongest binding free energies onto the Q 276 [I 277 ]I 278 , Q 351 [S 352 ]K 353 , and N 368 [K 369 ]K 370 sites of PSP than the other explored tracers, indicating a solid preference for vdW and cation−π interactions. Our results also reproduced known preferences of tracers, namely, that MK6240 binds better to AD tau than CBD tau and PSP tau and that CBD2115, PI2620, and PMPBB3 are 4R tau binders. These findings fill in the well-sought-after knowledge gap in terms of these tracers' potential binding mechanisms and will be important for the design of highly selective novel PET tracers for tauopathies.

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Section: Resultssupporting

confidence: 86%

Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

Li,

Kumar,

Långström

et al. 2023

ACS Chem. Neurosci.

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“…Fox Foundation and contained frequent α-synuclein aggregates and no other detectable aggregated amyloid species. The frozen tissue blocks were prepared for the binding assays as previously described 47 , 48 , except that equal quantities of the homogenates of three AD brains (AD1-AD3, Table S1 ) were pooled, as were homogenates from three PSP brains (PSP1-PSP3), three CBD brains (CBD1-CBD3), three Pick’s brains (PiD1-PiD3), and 4 PD brains (PD1-PD4) in order to help minimize the inter-subject variability within the different neuropathological groups. Individual subcortical brain tissues from a PSP subject (PSP4) and a CBD subject (CBD4), as well as with the middle frontal cortex of a control subject, were prepared for the binding assays as previously described 47 , 48 .…”

Section: Methodsmentioning

confidence: 99%

“…Tritium-labeled radioligand binding assays utilized AD, PSP, CBD, PiD, PD, or PD brain homogenates to determine equilibrium dissociation constant ( K d ) values and were performed as previously described 48 , 49 .…”

Section: Methodsmentioning

confidence: 99%

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies

Lindberg,

Murrell,

Tong

et al. 2024

Nat Commun

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Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

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“…The equilibrium inhibition constant (K i ) values of the unlabelled compounds (asyn-44 derivatives as well as tau ligands) were determined versus tritium-labelled asyn-44 according to our published methods. [21] Frozen aliquots (À 80 °C) of homogenized human PD (asyn-44 derivatives) or AD (tau ligands) tissue (10 mg/ mL in phosphate buffered saline) were thawed and diluted in 50 mM tris buffer (pH = 7.0) to 1 mg/mL. The unlabelled competitors were dissolved in DMSO at a concentration of 400 μM and diluted to 20 μM with tris buffer, resulting in a 5 % DMSO solution in tris buffer.…”

Section: In Vitro Competition (K I ) Assaysmentioning

confidence: 99%

Development of Pyridothiophene Compounds for PET Imaging of α‐Synuclein

Pees,

Tong,

Birudaraju

et al. 2024

Chemistry A European J

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Aggregated α‐synuclein (α‐syn) protein is a pathological hallmark of Parkinson’s disease (PD) and Lewy body dementia (LBD). Development of positron emission tomography (PET) radiotracers to image α‐syn aggregates has been a longstanding goal. We the pyridothiophene scaffold for α‐syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn‐44; Kd = 1.85 nM) were synthesized and screened against [3H]asyn‐44 in competitive binding assays using post‐mortem PD brain homogenates. Equilibrium inhibition constant (Ki) values of the most potent compounds were determined, of which three had Ki's between 12‐15 nM. An autoradiography study confirmed that [3H]asyn‐44 is promising for imaging multiple system atrophy and PD. Fluorine‐18 labelled asyn‐44 was synthesized in 6±2% radiochemical yield (decay‐corrected, n=5) with a molar activity of 263±121 GBq/µmol. Preliminary PET imaging of [18F]asyn‐44 in rats showed high initial brain uptake (>1.5 standardized uptake value (SUV)), moderate washout (~0.4 SUV at 60 min), and low variability. Radiometabolite analysis showed 60‐80% parent tracer in the brain after 30 and 60 mins. While [18F]asyn‐44 displayed good in vitro properties and acceptable brain uptake, troublesome radiometabolites precluded further PET imaging studies. The development of additional pyridothiophene derivatives are underway, with the goal of attaining improved affinity and metabolic stability.

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In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers

Cited by 8 publications

References 56 publications

Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies

Development of Pyridothiophene Compounds for PET Imaging of α‐Synuclein

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