title: Monoamine oxidase B inhibitor, selegiline, reduces18F-THK5351 uptake in the human brain.
abstract: BACKGROUND
  18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on18F-THK5351 brain uptake using PET and autoradiography.
  
  
  METHODS
  Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline18F-AZD4694 and18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third18F-THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region.18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline.
  
  
  RESULTS
  At baseline,18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on18F-THK5351 uptake.
  
  
  CONCLUSIONS
  These results indicate that the interpretation of18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of18F-THK5351 scans using reference region methods.
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.|Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.|Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Kok Pin
authors.initials: KP
authors.lastname: Ng
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Tharick A
authors.initials: TA
authors.lastname: Pascoal
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Sulantha
authors.initials: S
authors.lastname: Mathotaarachchi
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Therriault
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Min Su
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Shin
authors.affiliation: Montreal Neurological Institute/Hospital, Department of Pathology, McGill University Hospital Centre, 3801 University Street, Montreal, Québec, H3A 2B4, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Guiot
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.affiliation: McConnell Brain Imaging Centre, McGill University, 3801 University Street, Montreal, Québec, H3A 2B4, Canada.
authors.forename: Gassan
authors.initials: G
authors.lastname: Massarweh
authors.affiliation: McConnell Brain Imaging Centre, McGill University, 3801 University Street, Montreal, Québec, H3A 2B4, Canada.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soucy
authors.affiliation: Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.affiliation: Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada. pedro.rosa@mcgill.ca.|Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada. pedro.rosa@mcgill.ca.|Montreal Neurological Institute, 3801 University Street, Montreal, Québec, H3A 2B4, Canada. pedro.rosa@mcgill.ca.|Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Québec, H3A 2B4, Canada. pedro.rosa@mcgill.ca.
authors.forename: Pedro
authors.identifier: http://orcid.org/0000-0001-9116-1376
authors.initials: P
authors.lastname: Rosa-Neto
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism; D000631:Aminopyridines / Q000493:pharmacokinetics*; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals; D012642:Selegiline / Q000494:pharmacology*; D013494:Supranuclear Palsy, Progressive / Q000000981:diagnostic imaging / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D005462:Fluorine Radioisotopes; C054369:MAPT protein, human; D008996:Monoamine Oxidase Inhibitors; D011804:Quinolines; D019275:Radiopharmaceuticals; C000608225:THK5351; D016875:tau Proteins; D012642:Selegiline; D008995:Monoamine Oxidase
keywords: 18F-THK5351 tau tracer; Alzheimer’s disease; Monoamine oxidase-B; Positron emission tomography; Selegiline