Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

Lindberg, Anton; Mossine, Andrew V.; Aliaga, Arturo; Hopewell, Robert; Massarweh, Gassan; Rosa‐Neto, Pedro; Shao, Xia; Bernard‐Gauthier, Vadim; Scott, Peter J. H.; Vasdev, Neil

doi:10.3389/fnins.2021.725873

Cited by 6 publications

(17 citation statements)

References 28 publications

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“…The results and hypothesis presented here support our preliminary PET imaging findings of high [ 11 C]MPC-6827 uptake in nonhuman primates with low CSF Aβ 42 that we previously shown to be associated with higher brain Aβ deposition [ 47 ], and therefore potentially more destabilized MTs, versus nonhuman primates with high CSF Aβ 42 (and presumably low brain Aβ deposition, and healthy MTs) in vivo [ 48 ]. The same finding has been independently replicated in human brain (post-mortem) and rodents by other groups [ 41 , 49 ]. Notably, increased [ 11 C]MPC-6827 autoradiography binding in postmortem human AD brain compared to controls [ 41 ] is consistent with the results in tau KO mice here.…”

Section: Discussionsupporting

confidence: 66%

“…The same finding has been independently replicated in human brain (post-mortem) and rodents by other groups [ 41 , 49 ]. Notably, increased [ 11 C]MPC-6827 autoradiography binding in postmortem human AD brain compared to controls [ 41 ] is consistent with the results in tau KO mice here. Given that tau KO mice do not accumulate Aβ plaque or tau deposition, neuronal loss, neuroinflammation or other pathological features of AD, our data indicate that radiotracer uptake does not reflect these pathologies, but instead is altered by MT stability.…”

Section: Discussionsupporting

confidence: 66%

“…Lindberg et.al. recently reported differential uptake in postmortem human AD brains compared to age-matched controls using autoradiography [ 41 ]. The current evidence strongly supports its clinical utility; however the implications of [ 11 C]MPC-6827 uptake in normal and disease conditions are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

et al. 2022

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Background Microtubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer’s disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [11C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here. Methods In vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [11C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [11C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [11C]MPC-6827. Additionally, α, β, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays. Results Cell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [11C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower β tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [11C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results. Conclusions Collectively, our data indicate that [11C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [11C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 66%

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Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

et al. 2022

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“…107 Labeling in different positions (3methoxy-vs 10-methoxy-) showed no difference in the compound distribution. 105 3.6. N,N-Dimethylphenethylamine 3.6.1.…”

Section: Alkaloidsmentioning

confidence: 99%

“…Activity in the placenta reached a maximum within a few minutes, and rapid fetal liver accumulation was observed. 105 In 1989, [methyl-11 C]morphine was imaged in the spinal canal of nine rhesus monkeys. The tracer was administered at different spinal cord levels at different times, and kinetic measurements were performed up to 120 min post-tracer administration with plasma and cerebrospinal fluid samples.…”

Section: Clinical Studiesmentioning

confidence: 99%

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

et al. 2022

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The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

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Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

Damuka,

Irmen,

Krizan

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONMicrotubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau‐based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT‐PET radiotracer, [11C]MPC‐6827, in multiple established AD mouse models.METHODSLongitudinal PET, biodistribution, autoradiography, immunohistochemistry, and behavioral studies were conducted at multiple time points in APPswe/PSEN1dE9 (APP/PS1), P301S‐PS19 (P301S), 5xFAD, and age‐matched control mice.RESULTSLongitudinal [11C]MPC‐6827 brain imaging showed significant increases in APP/PS1, P301S, and 5xFAD mice compared to controls. Longitudinal MT‐PET correlated positively with biodistribution, autoradiography, and immunohistochemistry results and negatively with behavior data.DISCUSSIONOur study demonstrated significant longitudinal [11C]MPC‐6827 PET increases in multiple AD mouse models for the first time. Strong correlations between PET and biomarker data underscored the interplay of MT destabilization, amyloid, and tau pathology in AD. These results suggest [11C]MPC‐6827 PET as a promising tool for monitoring MT dysregulation early in AD progression.Highlights Longitudinal positron emission tomography (PET) imaging studies using [11C]MPC‐6827 in multiple established Alzheimer's disease (AD) mouse models revealed an early onset of microtubule dysregulation, with significant changes in brain radiotracer uptake evident from 2 to 4 months of age. Intra‐group analysis showed a progressive increase in microtubule dysregulation with increasing AD burden, supported by significant correlations between PET imaging data and biodistribution, autoradiography, and molecular pathological markers. [11C]MPC‐6827 PET imaging demonstrated its efficacy in detecting early microtubule alterations preceding observable behavioral changes in AD mouse models, suggesting its potential for early AD imaging. The inclusion of the 5xFAD mouse model further elucidated the impact of amyloid beta (Aβ) toxicity on inducing tau hyperphosphorylation‐mediated microtubule dysregulation, highlighting the versatility of [11C]MPC‐6827 in delineating various aspects of AD pathology. Our study provides immediate clarity on high uptake of the microtubule‐based radiotracer in AD brains in a longitudinal setting, which directly informs clinical utility in Aβ/tau‐based studies.

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Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

Cited by 6 publications

References 28 publications

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

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Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

Cited by 6 publications

References 28 publications

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [11C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

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Product

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Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology