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.
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.
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.
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.
Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, et al. 18F-THK5351: a novel PET radiotracer for imaging neurofibrillary pathology in Alzheimer’s disease. J Nucl Med. 2015;57:1–43.
Lee MK, Hwang BY, Lee SA, Oh GJ, Choi WH, Hong SS, et al. 1-methyl-2-undecyl-4(1H)-quinolone as an irreversible and selective inhibitor of type B monoamine oxidase. Chem Pharm Bull (Tokyo). 2003;51:409–11. CrossRef
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment. J. Am. Geriatr. Soc. Blackwell Science Inc; 2005;53:695–9.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 2011;77:333. CrossRef
Ad-Dab’bagh Y, Lyttelton O, Muehlboeck JS, Lepage C, Einarson D, Mok K, et al. The CIVET image-processing environment: a fully automated comprehensive pipeline for anatomical neuroimaging research. Proc. 12th Annu. Meet. Organ. Hum. Brain Mapp. 2006. p. 2266.
Pascoal TA, Mathotaarachchi S, Mohades S, Benedet AL, Chung C-O, Shin M, et al. Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol. Psychiatry. Nature Publishing Group; 2017;22:306–11.
Parent MJ, Bedard M-A, Aliaga A, Minuzzi L, Mechawar N, Soucy J-P, et al. Cholinergic depletion in Alzheimer’s disease shown by [ 18F]FEOBV autoradiography. Int J Mol Imaging. 2013;2013:1–6. CrossRef
Saura J, Andrés N, Andrade C, Ojuel J, Eriksson K, Mahy N, et al. Biphasic and region-specific MAO-B response to aging in normal human brain. Neurobiol Aging. 1980;18:497–507. CrossRef
Takano A, Halldin C, Farde L. Neuroimaging in psychiatric drug development and radioligand development for new targets. PET SPECT Psychiatry. Berlin, Heidelberg: Springer Berlin Heidelberg; 2014. p. 3–14.
Freedman NMT, Mishani E, Krausz Y, Weininger J, Lester H, Blaugrund E, et al. In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using (11)C-l-deprenyl and PET. J Nucl Med. 2005;46:1618–24. PubMed
Ishiki A, Harada R, Okamura N, Tomita N, Rowe CC, Villemagne VL, et al. Tau imaging with [ 18 F]THK-5351 in progressive supranuclear palsy. Eur. J. Neurol. 2017;24:130–6.
Bench CJ, Price GW, Lammertsma AA, Cremer JC, Luthra SK, Turton D, et al. Measurement of human cerebral monoamine oxidase type B (MAO-B) activity with positron emission tomography (PET): a dose ranging study with the reversible inhibitor Ro 19-6327. Eur J Clin Pharmacol. 1991;40:169–73. CrossRefPubMed
- Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain
Kok Pin Ng
Tharick A. Pascoal
Min Su Kang
Robert A. Comley
- BioMed Central