Majken Borup Thomsen1, Anna Christina Schacht1, Aage Kristian Olsen Alstrup1, Jan Jacobsen1, Thea Pinholt Lillethorup1, Simone Larsen Bærentzen1,2, Ove Noer1, Dariusz Orlowski3, Betina Elfving2, Heidi Kaastrup Müller2, David J Brooks1,4, Anne M Landau5,6. 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. 5. Department of Nuclear Medicine and PET, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 165, J, 8200, Aarhus N, Denmark. alandau@clin.au.dk. 6. Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. alandau@clin.au.dk.
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.
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.