Quantitative analysis of binding sites for 9‐fluoropropyl‐(+)‐dihydrotetrabenazine ([<sup>18</sup>F]AV‐133) in a MPTP‐lesioned PD mouse model

Chao, Ko-Ting; Tsao, Hsin-Hsin; Weng, Yi-Hsin; Hsiao, Ing‐Tsung; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu‐Chen; Kung, Mei‐Ping; Lin, Kun-Ju

doi:10.1002/syn.21572

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…Bohnen and colleagues demonstrated that striatal C11-dihydrotetrabenazine binding correlated reliably to clinically rated (UPDRSIII) motor deficits in PD patients [133]. Another VMAT2 radioligand, F-18-AV-133 (a tetrabenazine derivative), is also now used to study nigrostriatal degeneration [142, 143]. While VMAT2 radioligand binding conveniently correlates to nigrostriatal denervation, it does not provide direct evidence of vesicular function or VMAT2 activity.…”

Section: Vmat2 Imaging In Pdmentioning

confidence: 99%

Vesicular Integrity in Parkinson’s Disease

Alter

Lenzi

Bernstein

et al. 2013

Curr Neurol Neurosci Rep

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The defining motor characteristics of Parkinson’s disease (PD) are mediated by the neurotransmitter dopamine (DA). Dopamine molecules spend most of their lifespan stored in intracellular vesicles awaiting release and very little time in the extracellular space or the cytosol. Without proper packaging of transmitter and trafficking of vesicles to the active zone, dopamine neurotransmission cannot occur. In the cytosol, dopamine is readily oxidized; excessive cytosolic dopamine oxidation may be pathogenic to nigral neurons in PD. Thus, factors that disrupt vesicular function may impair signaling and increase the vulnerability of dopamine neurons. This review outlines the many mechanisms by which disruption of vesicular function may contribute to the pathogenesis of PD. From direct inhibition of dopamine transport into vesicles by pharmacological or toxicological agents to alterations in vesicle trafficking by PD-related gene products, variations in the proper compartmentalization of dopamine can wreak havoc on a functional dopamine pathway. Findings from patient populations, imaging studies, transgenic models, and mechanistic studies will be presented to document the relationship between impaired vesicular function and vulnerability of the nigrostriatal dopamine system. Given the deleterious effects of impaired vesicular function, strategies aimed at enhancing vesicular function may be beneficial in the treatment of PD.

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Section: Vmat2 Imaging In Pdmentioning

confidence: 99%

Vesicular Integrity in Parkinson’s Disease

Alter

Lenzi

Bernstein

et al. 2013

Curr Neurol Neurosci Rep

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“…Two irregular regions of interest encompassing the whole right and left striatum were drawn on four consecutive slices through the striatum, and the background was readily identifi ed and delineated on the cerebellum guided by detailed CT images and with reference to a stereotaxic brain atlas [26,27] . The results are expressed as SUr, calculated as: (mean striatal uptake − mean cerebellar uptake)/mean cerebellar uptake [22] , and dopaminergic denervation severity (DS) after MPTP treatment, calculated from SUr: (SUr baseline − SUr lesioned )/ SUr baseline [28,29] .…”

Section: Pet Image Acquisition and Analysismentioning

confidence: 99%

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

et al. 2013

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The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson's disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[ 18 F] fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]AV-133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [ 18 F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These

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“…The small animal 18 F-FP-(+)-DTBZ PET imaging followed a previously published protocol [38], and all PET images were acquired on a preclinical Inveon PET system (Siemens Medical Solutions, Knoxville, TN, USA). Each mouse was subjected to a 20-min static scan under isoflurane anesthesia (1.5% in oxygen gas) 30 min after receiving a single bolus injection of 18 F-FP-(+)-DTBZ (22.76 ± 0.45 MBq in 0.1 mL saline) through a tail vein.…”

Section: Methodsmentioning

confidence: 99%

“…The built-in volume of interests (VOIs) of the striatum and the cerebellum from the MRI template were applied to normalised PET images for quantification. The striatal specific uptake ratio (SUr) was calculated as [(uptake in striatum − uptake in cerebellum)/ (uptake in cerebellum)], where the cerebellum was used as the reference region [38]. …”

Section: Methodsmentioning

confidence: 99%

Quantitative analysis of the therapeutic effect of magnolol on MPTP-induced mouse model of Parkinson’s disease using in vivo 18F-9-fluoropropyl-(+)-dihydrotetrabenazine PET imaging

et al. 2017

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18F-9-Fluoropropyl-(+)-dihydrotetrabenazine [18F-FP-(+)-DTBZ] positron emission tomography (PET) has been shown to detect dopaminergic neuron loss associated with Parkinson’s disease (PD) in human and neurotoxin-induced animal models. A polyphenol compound, magnolol, was recently proposed as having a potentially restorative effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 6-hydroxydopamine-treated animal models. In this study, 18F-FP-(+)-DTBZ PET was used to determine the therapeutic efficacy of magnolol in an MPTP–PD mouse model that was prepared by giving an intraperitoneally (i.p.) daily dose of 25 mg/kg MPTP to male C57BL/6 mice for 5 consecutive days. Twenty-minute static 18F-FP-(+)-DTBZ PET scans were performed before MPTP treatment and 5 days after the termination of MPTP treatment to set up the baseline control. Half of the MPTP-treated mice then received a daily dose of magnolol (10 mg/kg dissolved in corn oil, i.p.) for 6 days. 18F-FP-(+)-DTBZ PET imaging was performed the day after the final treatment. All 18F-FP-(+)-DTBZ PET images were analysed and the specific uptake ratio (SUr) was calculated. Ex vivo autoradiography (ARG) and corresponding immunohistochemistry (IHC) studies were conducted to confirm the distribution of dopaminergic terminals in the striatum. The striatal SUr ratios of 18F-FP-(+)-DTBZ PET images for the Sham, the MPTP, and the MPTP + Magnolol-treated groups were 1.25 ± 0.05, 0.75 ± 0.06, and 1.00 ± 0.11, respectively (n = 4 for each group). The ex vivo 18F-FP-(+)-DTBZ ARG and IHC results correlated favourably with the PET imaging results. 18F-FP-(+)-DTBZ PET imaging suggested that magnolol post-treatment may reverse the neuronal damage in the MPTP-lesioned PD mice. In vivo imaging of the striatal vesicular monoamine transporter type 2 (VMAT2) distribution using 18F-FP-(+)-DTBZ animal PET is a useful method to evaluate the efficacy of therapeutic drugs i.e., magnolol, for the management of PD.

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Quantitative analysis of binding sites for 9‐fluoropropyl‐(+)‐dihydrotetrabenazine ([¹⁸F]AV‐133) in a MPTP‐lesioned PD mouse model

Cited by 15 publications

References 26 publications

Vesicular Integrity in Parkinson’s Disease

Vesicular Integrity in Parkinson’s Disease

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

Quantitative analysis of the therapeutic effect of magnolol on MPTP-induced mouse model of Parkinson’s disease using in vivo 18F-9-fluoropropyl-(+)-dihydrotetrabenazine PET imaging

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Quantitative analysis of binding sites for 9‐fluoropropyl‐(+)‐dihydrotetrabenazine ([18F]AV‐133) in a MPTP‐lesioned PD mouse model

Cited by 15 publications

References 26 publications

Vesicular Integrity in Parkinson’s Disease

Vesicular Integrity in Parkinson’s Disease

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

Quantitative analysis of the therapeutic effect of magnolol on MPTP-induced mouse model of Parkinson’s disease using in vivo 18F-9-fluoropropyl-(+)-dihydrotetrabenazine PET imaging

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Quantitative analysis of binding sites for 9‐fluoropropyl‐(+)‐dihydrotetrabenazine ([¹⁸F]AV‐133) in a MPTP‐lesioned PD mouse model