Modeling [11C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region

Laurencin, Chloé; Lancelot, Sophie; Gobert, Florent; Redouté, Jérôme; Mérida, Inès; Iecker, Thibault; Mouton-Liger, François; Irace, Zacharie; Greusard, Elise; Lamberet, Ludovic; Bars, Didier Le; Costes, Nicolas; Ballanger, Bénédicte

doi:10.1016/j.neuroimage.2021.118328

Cited by 6 publications

(10 citation statements)

References 36 publications

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“…However, based on the paucity of striatal NA innervation, the pre-eminent distribution of α2C receptors in the striatum and their strong affinity for DA, it remains unclear if the striatal amphetamine-induced changes in ORM-13070 or yohimbine binding reflect changes in NA solely or, more likely, a combined NA-DA stimulation, which we propose is occurring in striatal areas, based on our combined PET and microdialysis data. In support, a recent human study investigated the potential of clonidine, an α2 agonist known to decrease catecholamine release, to increase [ 11 C]yohimbine binding, and reported increased binding in the striatum, amygdala and posterior cortical areas [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…A recent human study [ 40 ] suggested the use of a white matter reference region, specifically the corpus callosum, to replace invasive blood sampling for a kinetic analysis of [ 11 C]yohimbine binding. Although we attempted to validate this approach in our minipig dataset, the relatively small size of the minipig brain together with the suboptimal resolution of the PET/CT scanner confounded the data and we could not delineate reliably in all of the pigs a white matter region in either the corpus callosum or central semiovale that was not subject to a variable amount of partial volume contamination by surrounding grey matter.…”

Section: Discussionmentioning

confidence: 99%

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Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release

et al. 2023

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The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [11C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [11C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [11C]yohimbine volumes of distribution (VT) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine VT, with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine VT. These data suggest that [11C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release

et al. 2023

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“…A condition for success is certainly to combine molecular imaging with clinical and behavioral analyses, yielding refined functional segregation [ 5 , 108 ]. Of particular interest is the new possibility to reliably investigate in α2 density in vivo in large human samples [ 109 ]. Understanding the NA pathogenic mechanisms that might contribute to disease progression and associated complications is indeed a prerequisite for developing novel neuroprotective or efficient disease-modifying therapies with individually tailored care.…”

Section: Discussionmentioning

confidence: 99%

Noradrenaline and Movement Initiation Disorders in Parkinson’s Disease: A Pharmacological Functional MRI Study with Clonidine

Criaud

Laurencin

Poisson

et al. 2022

Cells

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Slowness of movement initiation is a cardinal motor feature of Parkinson’s disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 μg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson’s disease.

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“…Noradrenergic imaging is particularly challenging, given that current radiotracers derived from antidepressants are non-selective to the noradrenalin transporter (NET), but also bind to DAT and SERT [ 94 ]. However, new, more specific, PET tracers are developed, such as for alpha2-adrenoreceptors [ 95 ].…”

Section: Neurotransmitter Imagingmentioning

confidence: 99%

Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

et al. 2022

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Neurodegenerative parkinsonian disorders are characterized by a great diversity of clinical symptoms and underlying neuropathology, yet differential diagnosis during lifetime remains probabilistic. Molecular imaging is a powerful method to detect pathological changes in vivo on a cellular and molecular level with high specificity. Thereby, molecular imaging enables to investigate functional changes and pathological hallmarks in neurodegenerative disorders, thus allowing to better differentiate between different forms of degenerative parkinsonism, improve the accuracy of the clinical diagnosis and disentangle the pathophysiology of disease-related symptoms. The past decade led to significant progress in the field of molecular imaging, including the development of multiple new and promising radioactive tracers for single photon emission computed tomography (SPECT) and positron emission tomography (PET) as well as novel analytical methods. Here, we review the most recent advances in molecular imaging for the diagnosis, prognosis, and mechanistic understanding of parkinsonian disorders. First, advances in imaging of neurotransmission abnormalities, metabolism, synaptic density, inflammation, and pathological protein aggregation are reviewed, highlighting our renewed understanding regarding the multiplicity of neurodegenerative processes involved in parkinsonian disorders. Consequently, we review the role of molecular imaging in the context of disease-modifying interventions to follow neurodegeneration, ensure stratification, and target engagement in clinical trials.

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Modeling [11C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region

Cited by 6 publications

References 36 publications

Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release

Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release

Noradrenaline and Movement Initiation Disorders in Parkinson’s Disease: A Pharmacological Functional MRI Study with Clonidine

Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

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