Preclinical PET Studies of [ 11 C]UCB-J Binding in Minipig Brain
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RESEARCH ARTICLE
Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain Majken Borup Thomsen,1 Anna Christina Schacht,1 Aage Kristian Olsen Alstrup,1 Jan Jacobsen,1 Thea Pinholt Lillethorup,1 Simone Larsen Bærentzen,1,2 Ove Noer,1 Dariusz Orlowski,3 Betina Elfving,2 Heidi Kaastrup Müller,2 David J. Brooks,1,4 Anne M. Landau 1,2 1
Department of Nuclear Medicine and PET, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 165, J, 8200, Aarhus N, Denmark 2 Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark 3 Center for Experimental Neuroscience (CENSE), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark 4 Institute of Translational and Clinical Research, Faculty of Medical Science, Newcastle upon Tyne University, Newcastle upon Tyne, UK
Abstract Purpose: Loss of neuronal synapse function is associated with a number of brain disorders. The [11C]UCB-J positron emission tomography (PET) tracer allows for in vivo examination of synaptic density, as it binds to synaptic vesicle glycoprotein 2A (SV2A) expressed in presynaptic terminals. Here, we characterise [11C]UCB-J imaging in Göttingen minipigs. Procedures: Using PET imaging, we examined tracer specificity and compared kinetic models. We explored the use of a standard blood curve and centrum semiovale white matter as a reference region. We compared in vivo [11C]UCB-J PET imaging to in vitro autoradiography, Western blotting and real-time quantitative polymerase chain reaction. Results: The uptake kinetics of [11C]UCB-J could be described using a 1-tissue compartment model and blocking of SV2A availability with levetiracetam showed dose-dependent specific binding. Population-based blood curves resulted in reliable [11C]UCB-J binding estimates, while it was not possible to use centrum semiovale white matter as a non-specific reference region. Brain [11C]UCB-J PET signals correlated well with [3H]UCB-J autoradiography and SV2A protein levels. Conclusions: [11C]UCB-J PET is a valid in vivo marker of synaptic density in the minipig brain, with binding values close to those reported for humans. Minipig models of disease could be valuable for investigating the efficacy of putative neuroprotective agents for preserving synaptic function in future non-invasive, longitudinal studies. Key words: Autoradiography, [11C]UCB-J PET, Minipig, Positron emission tomography, Synaptic density, Synaptic vesicle 2A
Introduction Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01506-8) contains supplementary material, which is available to authorized users. Correspondence to: Anne Landau; e-mail: [email protected]
Loss of synaptic function is associated with stroke, hippocampal sclerosis causing focal epilepsy and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, as well as psychiatric disorders including schizophrenia and endogenous
Thomsen M.B. et al.: [11C]UCB-J binding in minipig brain
depression
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