In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption

Kumar, J.S. Dileep; Molotkov, Andrei; Salling, Michael C.; Carberry, Patrick; Prabhakaran, Jaya; Castrillon, John; Mintz, Akiva

doi:10.1007/s43440-021-00311-6

Cited by 4 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%

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%

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

et al. 2022

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“…In recent years, the microtubule cytoskeleton has emerged as a relevant molecular substrate for the pervasive effects of alcohol. Several studies in rodent and human brain samples have shown that chronic alcohol exposure alters the abundance and acetylation of tubulin isotypes, as well as proteins known to regulate microtubule stability and dynamics, in the prefrontal cortex (PFC), hippocampus (Hipp), and ventral striatum [ 6 – 13 ]. An elegant demonstration of the functional significance of these changes was provided for collapsin response mediator protein-2 (CRMP-2), a microtubule-binding protein whose translation is increased in the nucleus accumbens following excessive alcohol consumption [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

Macedo

Kreifeldt

Goulding

et al. 2023

Neuropsychopharmacol.

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Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice. There was a complex interaction between the effects of MAP4343 and alcohol on affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.

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“…11 C]MPC-6827 was performed using our previously established procedure[15][16][17]. All animal experiments were carried out with the approval of the laboratories and bred and maintained at CUMC[18, 19].…”

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confidence: 99%

“…All animal experiments were carried out with the approval of the laboratories and bred and maintained at CUMC[18, 19]. Dynamic microPET scans (30 or 55 min) were performed on a Siemens Inveon microPET after tail vein administration of [ 11 C]MPC-6827 (1.85 ± 0.37 MBq, 200 µL volume)[17]. 9.1.0.…”

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confidence: 99%

Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models

et al. 2022

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Background: Microtubules are abundant in brain and their malfunctioning occurs in the early to advanced stages of neurodegenerative disorders. At present there is no in vivo test available for a definitive diagnosis of most of the neurodegenerative disorders.Herein, we present the microPET imaging of microtubules using our recently reported Positron Emission Tomography (PET) tracer, [ 11 C]MPC-6827, in transgenic mice models of tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A) and compared to corresponding age matched controls. Methods: Automated synthesis of [ 11 C]MPC-6827 was achieved in a GE-FX2MeI/FX2M radiochemistry module. In vivo PET imaging studies of [ 11 C]MPC-6827 (3.7+0.8 MBq)were performed in rTg4510 and SOD1*G93A mice groups and their corresponding littermates (n=5 per group). Dynamic PET images were acquired using a microPET Inveon system (Siemens, Germany) at 55 minutes for rTg4510 and 30 minutes for SOD1*G93A and corresponding controls. PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain was measured as %ID/g over time to generate standardized uptake values (SUV) and time-activity curves (TACs).Results: [ 11 C]MPC-6827 exhibit a trend of lower tracer binding in mouse models of Alzheimer's disease (tau pathology, line rTg4510) and Amyotrophic Lateral Sclerosis (line SOD1*G93A) compared to wild type littermates. Conclusions:Our finding indicates a trend of loss of microtubule binding of [ 11 C]MPC-6827 in the whole brain of AD and ALS transgenic mice models compared to control mice.The pilot studies described herein show that [ 11 C]MPC-6827 could be used as a PET ligand for preclinical and human brain imaging of Alzheimer's disease, ALS and other neurodegenerative diseases.

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In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption

Cited by 4 publications

References 24 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

Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models

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