Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain

Thomsen, Majken Borup; Schacht, Anna Christina; Alstrup, Aage Kristian Olsen; Jacobsen, Jørgen; Lillethorup, Thea Pinholt; Bærentzen, Simone Larsen; Noer, Ove; Orłowski, Dariusz; Elfving, Betina; Müller, Heidi Kaastrup; Brooks, David J.; Landau, Anne M.

doi:10.1007/s11307-020-01506-8

Cited by 12 publications

(7 citation statements)

References 40 publications

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“…[ 11 C]UCB-J has now been used in monkeys ( Nabulsi et al, 2016 ), pigs ( Thomsen et al, 2020 ), mice ( Bertoglio et al, 2020 ), rats ( Thomsen et al, 2021b ), and humans ( Finnema et al, 2016 ) and show favourable brain penetration, fast uptake and acceptable washout kinetics. In rats and mice, various kinetic modelling was performed using an arterial blood sampling scheme or image-derived input function (IDIF) from the heart ( Bertoglio et al, 2020 ; Glorie et al, 2020 ; Thomsen et al, 2021b ).…”

Section: Discussionmentioning

confidence: 99%

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Raval

Gudmundsen

Juhl

et al. 2021

Front. Synaptic Neurosci.

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Parkinson’s disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [11C]UCB-J and [18F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [11C]UCB-J binding and [18F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuit’s cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [11C]UCB-J and [18F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Raval

Gudmundsen

Juhl

et al. 2021

Front. Synaptic Neurosci.

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“…We performed tracer radiosynthesis of [ 11 C]UCB‐J as described previously 9,12,19 . All 49 subjects received an intravenous bolus of 500 MBq (±10%) 60 minutes before the scan.…”

Section: Methodsmentioning

confidence: 99%

“…We performed tracer radiosynthesis of [ 11 C]UCB-J as described previously. 9,12,19 All 49 subjects received an intravenous bolus of 500 MBq (AE10%) 60 minutes before the scan. All subjects were imaged on the ECAT Siemens High-Resolution Research Tomograph (HRRT) (Siemens/CTI, Knoxville, TN).…”

Section: Study Design and Participantsmentioning

confidence: 99%

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [¹¹C]UCB‐J and [¹⁸F]FDG PET Study

et al. 2023

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“…A large human cohort study revealed that imaging for 60- to 90- min is sufficient for the precise quantification of [ 11 C]UCB-J specific binding ( Naganawa et al, 2021a ). Preclinical studies have been performed to evaluate [ 11 C]UCB-J PET in different animal models, including mice ( Bertoglio et al, 2020 ), rats ( Thomsen et al, 2021b ) and minipigs ( Thomsen et al, 2020 ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain

Cited by 12 publications

References 40 publications

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [¹¹C]UCB‐J and [¹⁸F]FDG PET Study

Synaptic Vesicle Glycoprotein 2A: Features and Functions

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Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain

Cited by 12 publications

References 40 publications

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11C]UCB‐J and [18F]FDG PET Study

Synaptic Vesicle Glycoprotein 2A: Features and Functions

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Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [¹¹C]UCB‐J and [¹⁸F]FDG PET Study