title: Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195.
abstract: (11)C-PBR28 is a second-generation translocator protein (TSPO) tracer with characteristics supposedly superior to the most commonly used tracer for neuroinflammation, (R)-(11)C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of (11)C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aimed to evaluate (11)C-PBR28 as a tool for detection and quantification of neuroinflammation in preclinical research and to compare its imaging properties with (R)-(11)C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or 7 d after virus inoculation, a dynamic (11)C-PBR28 or (R)-(11)C-PK11195 PET scan with arterial blood sampling was obtained. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest and a voxel-based approach. Volume-of-interest- and voxel-based analysis of (11)C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. (11)C-PBR28 was metabolized faster than (R)-(11)C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in detecting neuroinflammation. The binding potential (BPND) of (11)C-PBR28 was significantly higher (P < 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%), and hypothalamus (49%) in HSE rats than in control rats, whereas (R)-(11)C-PK11195 showed a higher BPND only in the medulla (32%). The BPND in control animals was not significantly different between tracers, suggesting that the nonspecific binding of both tracers is similar. (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in the detection of TSPO overexpression in the HSE rat model, because more brain regions with significantly increased tracer uptake could be found, irrespective of the data analysis method used. These results suggest that (11)C-PBR28 should be able to detect more subtle changes in microglial activation in preclinical models of neuroinflammation.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Parente
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Instituto de Geriatria e Gerontologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brasil; and.
authors.forename: Paula Kopschina
authors.initials: PK
authors.lastname: Feltes
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Vállez García
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jurgen W A
authors.initials: JW
authors.lastname: Sijbesma
authors.affiliation: Instituto de Geriatria e Gerontologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brasil; and Instituto do Cérebro do Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brasil.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Moriguchi Jeckel
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik F J
authors.initials: EF
authors.lastname: de Vries
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands j.doorduin@umcg.nl.
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
mesh_terms: D000818:Animals; D001692:Biological Transport; D004195:Disease Models, Animal; D020803:Encephalitis, Herpes Simplex / Q000000981:diagnostic imaging / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007546:Isoquinolines / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C526315:(methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine; D007546:Isoquinolines; D011743:Pyrimidines; C037850:PK 11195
keywords: herpes simplex encephalitis; neuroinflammation; pharmacokinetic analysis; positron emission tomography; rat model