title: Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models.
abstract: Abnormal accumulation of tau aggregates in the brain is one of the hallmarks of Alzheimer disease neuropathology. We visualized tau deposition in vivo with the previously developed 2-arylquinoline derivative (18)F-THK5117 using small-animal PET in conjunction with autoradiography and immunohistochemistry gold standard assessment in 2 transgenic mouse models expressing hyperphosphorylated tau. Small-animal PET recordings were obtained in groups of P301S (n = 11) and biGT mice (n = 16) of different ages, with age-matched wild-type (WT) serving as controls. After intravenous administration of 16 ± 2 MBq of (18)F-THK5117, a dynamic 90-min emission recording was initiated for P301S mice and during 20-50 min after injection for biGT mice, followed by a 15-min transmission scan. After coregistration to the MRI atlas and scaling to the cerebellum, we performed volume-of-interest-based analysis (SUV ratio [SUVR]) and statistical parametric mapping. Small-animal PET results were compared with autoradiography ex vivo and in vitro and further validated with AT8 staining for neurofibrillary tangles. SUVRs calculated from static recordings during the interval of 20-50 min after tracer injection correlated highly with estimates of binding potential based on the entire dynamic emission recordings (R = 0.85). SUVR increases were detected in the brain stem of aged P301S mice (+11%; P < 0.001) and in entorhinal/amygdaloidal areas (+15%; P < 0.001) of biGT mice when compared with WT, whereas aged WT mice did not show increased tracer uptake. Immunohistochemical tau loads correlated with small-animal PET SUVR for both P301S (R = 0.8; P < 0.001) and biGT (R = 0.7; P < 0.001) mice, and distribution patterns of AT8-positive neurons matched voxelwise statistical parametric mapping analysis. Saturable binding of the tracer was verified by autoradiographic blocking studies. In the first dedicated small-animal PET study in 2 different transgenic tauopathy mouse models using the tau tracer (18)F-THK5117, the temporal and spatial progression could be visualized in good correlation with gold standard assessments of tau accumulation. The serial small-animal PET method could afford the means for preclinical testing of novel therapeutic approaches by accommodating interanimal variability at baseline, while detection thresholds in young animals have to be considered.
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brendel
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jaworska
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Probst
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Overhoff
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Korzhova
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Janette
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Tohoku University, Sendai, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.affiliation: Tohoku University, Sendai, Japan.
authors.forename: Yukitsuka
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Experimental Genetics Group LEGTEGG, KU-Leuven, Belgium.
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.affiliation: Tohoku University, Sendai, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany axel.rominger@med.uni-muenchen.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001345:Autoradiography; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000737:chemistry; D011854:Radiochemistry; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000604726:6-((3-fluoro-2-hydroxy)propoxy)-2-(4-methylaminophenyl)quinoline; D000814:Aniline Compounds; D011804:Quinolines; D016875:tau Proteins
keywords: 18F-THK5117; Alzheimer’s disease; small animal PET; tauopathy; transgenic mice