title: Pharmacokinetic Evaluation of the Tau PET Radiotracer18F-T807 (18F-AV-1451) in Human Subjects.
abstract: 18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions.Methods:Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue.Results:The percentage of unmetabolized18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min).18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding.VTwas greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates ofVTin excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region-based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2= 0.97,P< 0.0001).Conclusion:18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80-100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dustin W
authors.initials: DW
authors.lastname: Wooten
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Guehl
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eline E
authors.initials: EE
authors.lastname: Verwer
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shoup
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Yokell
authors.affiliation: Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Nevena
authors.initials: N
authors.lastname: Zubcevik
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.affiliation: Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Boston, Massachusetts; and.|Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Zafonte
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Georges
authors.initials: G
authors.lastname: El Fakhri
authors.affiliation: Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts normandin@mgh.harvard.edu.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Normandin
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism*; D002243:Carbolines / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002243:Carbolines; C054369:MAPT protein, human; D019275:Radiopharmaceuticals; D016875:tau Proteins; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
keywords: 18F-T807; PET; kinetic modeling; pharmacokinetics; tau