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Alzheimers Res Ther. 2017 Mar 31;9(1):25. doi: 10.1186/s13195-017-0253-y.

Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain.

Author information

1
Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
2
Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.
3
Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada.
4
Montreal Neurological Institute/Hospital, Department of Pathology, McGill University Hospital Centre, 3801 University Street, Montreal, Québec, H3A 2B4, Canada.
5
AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, USA.
6
Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
7
McConnell Brain Imaging Centre, McGill University, 3801 University Street, Montreal, Québec, H3A 2B4, Canada.
8
Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
9
Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada. pedro.rosa@mcgill.ca.
10
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.
11
Montreal Neurological Institute, 3801 University Street, Montreal, Québec, H3A 2B4, Canada. pedro.rosa@mcgill.ca.
12
Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Québec, H3A 2B4, Canada. pedro.rosa@mcgill.ca.

Abstract

BACKGROUND:

18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-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 on 18F-THK5351 brain uptake using PET and autoradiography.

METHODS:

Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-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 third 18F-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 after 18F-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 reduced 18F-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 on 18F-THK5351 uptake.

CONCLUSIONS:

These results indicate that the interpretation of 18F-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 of 18F-THK5351 scans using reference region methods.

KEYWORDS:

18F-THK5351 tau tracer; Alzheimer’s disease; Monoamine oxidase-B; Positron emission tomography; Selegiline

PMID:
28359327
PMCID:
PMC5374697
DOI:
10.1186/s13195-017-0253-y
[Indexed for MEDLINE]
Free PMC Article

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