The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases
Abstract
Background: Lilly/Avid's AV‐1451 is one of the most advanced tau PET tracers in the clinic. Although results obtained in Alzheimer's disease patients are compelling, discrimination of tracer uptake in healthy individuals and patients with supranuclear palsy (PSP) is less clear as there is substantial overlap of signal in multiple brain regions. Moreover, accurate quantification of [18 F]AV‐1451 uptake in Alzheimer's disease may not be possible. Objectives: The aim of the present study was to characterize the in vitro binding of AV‐1451 to understand and identify potential off‐target binding that could explain the poor discrimination observed in PSP patients. Methods: [3 H]AV‐1451 and AV‐1451 were characterized in in vitro binding assays using recombinant and native proteins/tissues from postmortem samples of controls and Alzheimer's disease and PSP patients. Results: [3 H]AV‐1451 binds to multiple sites with nanomolar affinities in brain homogenates and to tau fibrils isolated from Alzheimer's disease or PSP patients. [3 H]AV‐1451 also binds with similarly high affinities in brain homogenates devoid of tau pathology. This unexpected binding was demonstrated to be because of nanomolar affinities of [3 H]AV‐1451 for monoamine oxidase A and B enzymes. Conclusions: High affinity of AV‐1451 for monoamine oxidase proteins may limit its utility as a tau PET tracer in PSP and Alzheimer's disease because of high levels of monoamine oxidase expression in brain regions also affected by tau deposition, especially if monoamine oxidase levels change over time or with a treatment intervention. © 2017 International Parkinson and Movement Disorder Society
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18F-AV-1451 can have other non-tau, non-TDP-43 targets such as neuromelanin and mono-amine oxidase, and such off-target binding is an important caveat in clinical studies using 18F-AV-1451.
“18F-AV-1451 can have other non-tau, non-TDP-43, targets such as neuromelanin (Marquié et al., 2015) and mono-amine oxidase (MAO) (Vermeiren et al., 2018), and such off-target binding is an important caveat in clinical studies using 18F-AV-1451 (Baker et al., 2019).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Vermeiren et al., 2018
Cites
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“The increased binding with age could be driven by AV-1451’s high affinity for MAOB, because the MAO-B expression level, for example, in the globus pallidus, increases with age.(20,28,29) MAO-A and -B protein levels were also reported to change in diseases such as AD and Huntington’s disease,(30-33) adding complexity t…”
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“Interestingly, off-target binding of tau-PET tracers are potentially attributed to MAO-A and/or MAO-B enzymes.(121) For example, binding to MAO-B in vivo in humans was recently demonstrated for another tau-PET tracer, [(18)F]THK5351, in which selegiline (MAO-B inhibitor) reduced the cortical PET signal by 40% in patie…”
BackgroundMueller, A., Bullich, S., Barret, O., Madonia, J., Berndt, M., Papin, C., Perrotin, A., Koglin, N., Kroth, H., Pfeifer, A., et al. (2019) · Journal of Nuclear Medicine · doi:10.2967/jnumed.119.236224 · Cited by 191 · see citing works
“Tissue-binding analyses with radiolabeled AV1451 demonstrated selective binding to tangles on AD brain tissue but not in other tauopathies (11).”
BackgroundInfluentialAmyloid and tau imaging biomarkers explain cognitive decline from late middle-age
Betthauser, T. J., Koscik, R. L., Jonaitis, E. M., Allison, S. L., Cody, K. A., Erickson, C. M., Rowley, H. A., Stone, C. K., Mueller, K. D., Clark, L. R., et al. (2019) · Brain · doi:10.1093/brain/awz378 · Cited by 174 · see citing works
“…(i.e. T807, AV-1451) for tau PET imaging, which is known to exhibit age-associated off-target binding in the brain (Gordon et al. , 2016; Choi et al. , 2018) with mechanisms and the spatial extent of non-tau flortaucipir binding yet to be fully characterized in vivo (Vermeiren et al. , 2018).”
The development and validation of tau PET tracers: current status and future directions
Okamura, N., Harada, R., Ishiki, A., Kikuchi, A., Nakamura, T., & Kudo, Y. (2018) · Clinical and Translational Imaging · doi:10.1007/s40336-018-0290-y · Cited by 183 · see citing works
Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue
Agüero, C., Dhaynaut, M., Normandin, M. D., Amaral, A. C. S., Guehl, N. J., Neelamegam, R., Marquié, M., Johnson, K. A., Fakhri, G. E., Frosch, M. P., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0686-6 · Cited by 173 · see citing works
“Controversy exists as to whether AV-1451 may also exhibit significant nonspecific binding to MAO enzymes [12, 15, 17, 30], as it has been recently demonstrated for other tau PET tracers like THK-5351 [13, 24].”
BackgroundTau positron emission tomography imaging in tauopathies: The added hurdle of off-target binding
Lemoine, L., Leuzy, A., Chiotis, K., Rodriguez-Vieitez, E., & Nordberg, A. (2018) · Alzheimer's & Dementia · doi:10.1016/j.dadm.2018.01.007 · Cited by 144 · see citing works
“Keywords: Tau PET; Off-target; AV-1451; THK5351; THK5117; THK5317; T807; MAO-B; MAO-A; Flortaucipir”
InfluentialNeuroimaging Advances in Parkinson's Disease and Atypical Parkinsonian Syndromes
Saeed, U., Lang, A. E., & Masellis, M. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.572976 · Cited by 153 · see citing works
“The 18F-AV-1451 tracer also shows an off-target binding to monoamine oxidase (MAO) A and B (312).”
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“Although 3H-flortaucipir binds to monoamine oxidase A (MAO-A) and B (MAO-B) in vitro (21), in vivo studies have yet to replicate 18F-flortaucipir binding to MAO-A or MAO-B (22).”
BackgroundNeuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Kaalund, S. S., Passamonti, L., Allinson, K., Green, O., Hong, Y. T., Fryer, T. D., Arnold, R., et al. (2020) · Brain · doi:10.1093/brain/awaa033 · Cited by 124 · see citing works
Tauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s Disease
Jie, C. V. M. L., Treyer, V., Schibli, R., & Mu, L. (2021) · Pharmaceuticals · doi:10.3390/ph14020110 · Cited by 111 · see citing works
“brain regions when comparing PSP patients with AD patients and healthy subjects [47].”
BackgroundResultImaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases
Endo, H., Ono, M., Takado, Y., Matsuoka, K., Takahashi, M., Tagai, K., Kataoka, Y., Hirata, K., Takahata, K., Seki, C., et al. (2020) · bioRxiv · doi:10.1101/2020.10.23.349860 · Cited by 103
McCluskey, S. P., Plisson, C., Rabiner, E. A., & Howes, O. D. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04488-0 · Cited by 121 · see citing works
Uzuegbunam, B. C., Librizzi, D., & Yousefi, B. H. (2020) · Molecules · doi:10.3390/molecules25040977 · Cited by 103 · see citing works
“Findings in which the THK-radiotracers and flortaucipir have been implicated following in vitro assessments [169,170,184,188].”
BackgroundNeuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy
Malpetti, M., Passamonti, L., Rittman, T., Jones, P. S., Vázquez Rodríguez, P., Bevan‐Jones, W. R., Hong, Y. T., Fryer, T. D., Aigbirhio, F. I., O'Brien, J. T., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25911 · Cited by 83 · see citing works
“The tracer also binds to nontau proteinopathies (ie, is positive in TDP43 pathology with C9orf72 mutations and semantic dementia(31)), and other targets, such as neuromelanin,(29) choroid plexus,(28) and monoamine oxidase (MAO).(32) However, “off-target” binding can neither fully account for [(18)F]AV-1451 signal in s…”
BackgroundMurugan, N., Chiotis, K., Rodriguez-Vieitez, E., Lemoine, L., Ågren, H., & Nordberg, A. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04305-8 · Cited by 82 · see citing works
“Although recent in vitro studies agree on the existence of such a cross-interaction [3, 13, 14, 40], the results of the in vivo studies have been equivocal, probably because of the blocking design used, with the administration of irreversible MAO-B inhibitors [12, 41].”
Evaluation of 18F-RO-948 PET for Quantitative Assessment of Tau Accumulation in the Human Brain
Kuwabara, H., Comley, R., Borroni, E., Honer, M., Kitmiller, K., Roberts, J., Gapasin, L., Mathur, A., Klein, G., & Wong, D. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.214437 · Cited by 72 · see citing works
“In addition, 3H-RO-948 lacks affinity to monoamine oxidase A and B (11), again in contrast to 18FAV1451 (39).”
ResultIn vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury
Gorgoraptis, N., Li, L. M., Whittington, A., Zimmerman, K. A., Maclean, L. M., McLeod, C., Ross, E., Heslegrave, A., Zetterberg, H., Passchier, J., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw1993 · Cited by 74 · see citing works
“Flortaucipir is relatively selective for tau, with no substantial binding to β-amyloid, α-synuclein or TDP43 in post-mortem brain tissue (12), although it also binds off-target to monoamine oxidases (15) as well as neuromelanin- and melanin-containing cells (12, 16).”
BackgroundInfluentialNeuroinflammation is linked to dementia risk in Parkinson’s disease
Kouli, A., Spindler, L. R. B., Fryer, T., Hong, Y. T., Malpetti, M., Aigbirhio, F., White, S., Camacho, M., O'Brien, J., & Williams-Gray, C. (2023) · Brain : a journal of neurology · doi:10.1093/brain/awad322 · Cited by 66 · see citing works
“42 Specifically, the greater binding in the PD participants may have been due to age-and possibly pathology-related neuromelanin and iron deposits, for which AV-1451 shows binding affinity.”
Tau Imaging in Neurodegenerative Diseases Using Positron Emission Tomography
Wang, Y. T., & Edison, P. (2019) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-019-0962-7 · Cited by 82 · see citing works
Tau and atrophy: domain-specific relationships with cognition
Initiative, A. D. N., Digma, L. A., Madsen, J. R., Reas, E. T., Dale, A. M., Brewer, J. B., & Banks, S. J. (2019) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0518-8 · Cited by 64 · see citing works
“FTP has been shown to exhibit off-target binding to choroid plexus in the areas adjacent to the hippocampus [61], to monoamine oxidases [62], and others.”
BackgroundNeuroimaging-pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy
Ishiki, A., Harada, R., Kai, H., Sato, N., Totsune, T., Tomita, N., Watanuki, S., Hiraoka, K., Ishikawa, Y., Funaki, Y., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0556-7 · Cited by 61 · see citing works
Overview of tau PET molecular imaging
Petersen, G. C., Roytman, M., Chiang, G. C.-Y., Li, Y., Gordon, M. L., & Franceschi, A. M. (2022) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001035 · Cited by 82 · see citing works
“In addition, flortaucipir has been found to bind to MAO A/B, compromising the tracer’s specificity in the brain where these enzymes are common [20].”
BackgroundBiomarkers for diseases with TDP-43 pathology
Steinacker, P., Barschke, P., & Otto, M. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.10.003 · Cited by 57 · see citing works
Aguero, C., Dhaynaut, M., Amaral, A., Moon, S.-H., Neelamegam, R., Scapellato, M., Carazo-Casas, C., Kumar, S., Fakhri, G. E., Johnson, K. A., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02672-z · Cited by 54 · see citing works
“Some studies have suggested that Flortaucipir but not MK-6240 or PI-2620 may bind with similar affinity to tau fibrils and MAO-A and/or B enzymes [53, 54] while others, including our own, point to low binding affinity of both Flortaucipir and MK-6240 to MAO enzymes [1, 59].”
BackgroundImaging of Reactive Astrogliosis by Positron Emission Tomography
Harada, R., Furumoto, S., Kudo, Y., Yanai, K., Villemagne, V. L., & Okamura, N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.807435 · Cited by 63 · see citing works
“In fact, validation studies of Aβ and tau PET tracers identified that some of them possess high binding affinity against MAO-B (Sur et al., 2010; Ng et al., 2017; Harada et al., 2018; Vermeiren et al., 2018; Drake et al., 2019).”
BackgroundBischof, G. N., Dodich, A., Boccardi, M., van Eimeren, T., Festari, C., Barthel, H., Hansson, O., Nordberg, A. K., Ossenkoppele, R., Sabri, O., et al. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-020-05156-4 · Cited by 53 · see citing works
“generation tau PET tracers to monoamine oxidase B (MAOB) has been shown in basal ganglia and thalamus for all tracers of the THK series, (11)C-PBB-3, and (18)F-AV-1451 [22, 23].”
BackgroundFichou, Y., Al‐Hilaly, Y. K., Devred, F., Smet‐Nocca, C., Tsvetkov, P. O., Verelst, J., Winderickx, J., Geukens, N., Vanmechelen, E., Perrotin, A., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0682-x · Cited by 63 · see citing works
Bollack, A., Pemberton, H., Collij, L. E., Markiewicz, P. J., Cash, D. M., Farrar, G., & Barkhof, F. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13158 · Cited by 49 · see citing works
“…non-specific binding in the choroid plexus, accurately quantifying tau binding in the hippocampus using 18 F-flortaucipir can be challenging, 154,155 but it may be mitigated with effective application of PVC. 156 Longitudinal trajectories at the regional level for amyloid…”
MethodIdentification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase.
Drake, L., Pham, J. M., Desmond, T., Mossine, A. V., Lee, S. J., Kilbourn, M., Koeppe, R., Brooks, A. F., & Scott, P. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00326 · Cited by 45 · see citing works
Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer’s disease cases
Malarte, M.-L., Nordberg, A., & Lemoine, L. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-020-05035-y · Cited by 41 · see citing works
“Unfortunately, first-generation tau PET tracers also demonstrated off-target binding: THK5117, THK5351 and AV-1451 bind to monoamine oxidase B (MAO-B) [12], AV-1451 binds to neuromelanin [13] and PBB3 binds to amyloid plaques and alpha-synuclein [14, 15].”
BackgroundNeuroimaging of Alzheimer’s disease: focus on amyloid and tau PET
Matsuda, H., Yoko, S., & Sato, N. (2019) · Japanese Journal of Radiology · doi:10.1007/s11604-019-00867-7 · Cited by 40 · see citing works
Kelberman, M. A., Keilholz, S. D., & Weinshenker, D. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.583421 · Cited by 43 · see citing works
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“Alternatively, it has been suggested [45, 46] that flor-”
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Imaging of Tau Pathology in Neurodegenerative Diseases: An Update
Beyer, L., & Brendel, M. (2020) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2020.12.004 · Cited by 42 · see citing works
“Compared to first-generation tau radiotracers, significantly lower off-target binding to MAO-A/B was observed 28-31 with [ 18 F]MK-6240, [ 18 F]JNJ067and [ 18 F]PI-2620 appearing to have the lowest relative affinity for MAO-B 32 .”
PET Imaging of Astrogliosis and Tau Facilitates Diagnosis of Parkinsonian Syndromes
Schönecker, S., Brendel, M., Palleis, C., Beyer, L., Höglinger, G., Schuh, E., Rauchmann, B., Sauerbeck, J., Rohrer, G., Sonnenfeld, S., et al. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00249 · Cited by 37 · see citing works
Wren, M. C., Lashley, T., Årstad, E., & Sander, K. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0535-z · Cited by 37 · see citing works
“It has now been confirmed that flortaucipir exhibits strong off-target binding to monoamine oxidase isoforms and pigment containing cells, predominantly expressed in the striatum and the substantia nigra, respectively [15, 23, 46].”
BackgroundCharacterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy
Weng, C.-C., Hsiao, I.-T., Yang, Q.-F., Yao, C.-H., Tai, C., Wu, M., Yen, T., Jang, M., & Lin, K.-J. (2020) · Molecules · doi:10.3390/molecules25071750 · Cited by 35 · see citing works
“However, the dominant binding was delineated from 18F-THK5351 in the brain regions such as the basal ganglia, thalamus, and brainstem and this tracer’s off-target binding to monoamine oxidase-B (MAO-B) has been verified [16,17].”
BackgroundHammes, J., Bischof, G. N., Bohn, K. P., Onur, O. A., Schneider, A., Fließbach, K., Hoenig, M. C., Jessen, F., Neumaier, B., Drzezga, A. E., et al. (2020) · Journal of Nuclear Medicine · doi:10.2967/jnumed.120.244061 · Cited by 36 · see citing works
“strength of 18F-flortaucipir to tau fibrils and monoamine oxidases (35).”
BackgroundWooten, D. W., Ortiz-Terán, L., Zubcevik, N., Zhang, X., Huang, C., Sepulcre, J., Atassi, N., Johnson, K. A., Zafonte, R., & Fakhri, G. E. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6178 · Cited by 30 · see citing works
“Studies have shown that [(18)F]AV-1451 binds to MAO-A and MAO-B; however, another study has shown MAO-B inhibitors are incapable of blocking [(18)F]AV-1451 uptake.(6,7,42) Additionally,”
BackgroundNeuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrumPreprint
Bevan-Jones, W. R., Cope, T., Jones, P. S., Passamonti, L., Hong, Y. T., Fryer, T., Arnold, R., Coles, J., Aigbirhio, F., Larner, A., et al. (2019) · bioRxiv · doi:10.1101/525642 · Cited by 30 · see citing works
“It is noted that this elevated [18F]AV-1451 binding is seen in a distribution that closely resembles that of neuropathology, suggesting potential binding to other proteins expressed by degenerating neurons or reactive glial cells, such as isoforms of monoamine oxidase (Vermeiren et al., 2018).”
PET Agents in Dementia: An Overview
van Waarde, A., Marcolini, S., Deyn, P. P. D., & Dierckx, R. (2021) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2020.12.008 · Cited by 38 · see citing works
Burnham, S. C., Iaccarino, L., Pontecorvo, M. J., Fleisher, A., Lu, M., Collins, E. C., & Devous, M. D. (2023) · Brain Communications · doi:10.1093/braincomms/fcad305 · Cited by 29 · see citing works
Evaluation of [18F]N-methyl-lansoprazole as a tau PET imaging agent in first-in-human studies
Kramer, V., Brooks, A. F., Haeger, A., Kuljiš, R., Rafique, W., Koeppe, R., Raffel, D., Frey, K., Amaral, H., Scott, P., et al. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00639 · Cited by 25 · see citing works
Mohammadi, Z., Alizadeh, H., Marton, J., & Cumming, P. D. (2023) · Biomolecules · doi:10.3390/biom13020290 · Cited by 28 · see citing works
Perani, D., Iaccarino, L., Lammertsma, A. A., Windhorst, A. D., Edison, P., Boellaard, R., Hansson, O., Nordberg, A. K., Jacobs, A. H., & IMBI Project (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.02.004 · Cited by 24 · see citing works
“Of note, a recent study has shown that selegiline, a monoamine oxidase B (MAO B) inhibitor, significantly reduces brain [18F]THK5351 uptake [164], whereas [18F]flortaucipir uptake seems to be not affected [165], and a recent in vitro study has reported similar nanomolar affinity of [18F]flortaucipir to both tau fibril…”
BackgroundHead-to-Head Comparison of Tau-PET Radioligands for Imaging TDP-43 in Post-Mortem ALS Brain
Knight, A. C., Morrone, C. D., Varlow, C., Yu, W. H., Mcquade, P. S., & Vasdev, N. (2022) · Molecular Imaging and Biology · doi:10.1007/s11307-022-01779-1 · Cited by 22 · see citing works
“4 nM) and MAO-B (21 ± 9 nM) [44] has been described and is not dissimilar from its binding affinity to tau in native brain tissue delineated by ARG [45].”
BackgroundEvaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy
Varlow, C., & Vasdev, N. (2022) · Journal of Nuclear Medicine · doi:10.2967/jnumed.122.264404 · Cited by 23 · see citing works
“The reported off-target binding of (3)H-flortaucipir to MAO-A and MAO-B presents a challenge for interpretation of specific binding quantitation and distribution in vitro, as binding of (3)H-flortaucipir to MAO-A/B has been reported with similar affinities to tau (31).”
BackgroundIkeda, A., Shimada, H., Nishioka, K., Takanashi, M., Hayashida, A., Li, Y., Yoshino, H., Funayama, M., Ueno, Y., Hatano, T., et al. (2019) · Movement Disorders · doi:10.1002/mds.27623 · Cited by 22 · see citing works
Künze, G., Kümpfel, R., Rullmann, M., Barthel, H., Brendel, M., Patt, M., & Sabri, O. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00291 · Cited by 21 · see citing works
Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases
Wilson, H., Politis, M., Rabiner, E. A., & Middleton, L. T. (2020) · Cells · doi:10.3390/cells9122581 · Cited by 34 · see citing works
“A main limitation of first-generation PET radioligands is the presence of off-target binding to neuromelanin and monoamine oxidase [142,143].”
Background[18F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer’s disease
Chiotis, K., Savitcheva, I., Poulakis, K., Saint-Aubert, L., Wall, A., Antoni, G., & Nordberg, A. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0815-4 · Cited by 21 · see citing works
Alster, P., Madetko‐Alster, N., Koziorowski, D., Królicki, L., Budrewicz, S. P., & Friedman, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00101 · Cited by 22 · see citing works
“, iron deposits, iron melanin, and hemorrhagic lesions (21, 22) It should be underlined, that another study stressed affinity of 18F-AV-1451PET to MAO-A (23) A different work questioned the usefulness of 18F-AV-1451-PET in the examination of 4 repeats (4R) tauopathies, as the authors interpreted the binding properties…”
BackgroundInfluentialThe Role of Amyloid- and Tau PET in the New Era of Alzheimer Disease Therapies
Chiotis, K., Wang, Y., Joie, R. L., & Rabinovici, G. D. (2025) · Journal of Nuclear Medicine · doi:10.2967/jnumed.124.268339 · Cited by 18 · see citing works
“For example, 18 F-fl ortauci-pir shows nontau-related binding in the basal ganglia, possibly related to monoamine oxidase B or iron binding ( 60 , 61 ), and in the choroid plexus, the latter complicating interpretation of the signal in the MTL ( 47 ).”
Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau
Chisholm, T. S., & Hunter, C. A. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00838 · Cited by 24 · see citing works
Relationship Between 18F-Flortaucipir Uptake and Histologic Lesion Types in 4-Repeat Tauopathies
Josephs, K., Tosakulwong, N., Weigand, S., Buciuc, M., Lowe, V., Dickson, D. W., & Whitwell, J. (2021) · Journal of Nuclear Medicine · doi:10.2967/jnumed.121.262685 · Cited by 20 · see citing works
“This latter explanation is supported by previous studies that have found evidence that 18 F-fl ortaucipir binds to neuromelanin and melanin-containing cells ( 3,18 ), iron ( 19 ), monoamine oxidase B inhibitors ( 20 ), and vascular structures ( 21 ), to name a few.”
ResultTauIQ: A Canonical Image Based Algorithm to Quantify Tau PET Scans
Whittington, A., Gunn, R. N., & Initiative, A. D. N. (2021) · Journal of Nuclear Medicine · doi:10.2967/jnumed.120.258962 · Cited by 24 · see citing works
“The nonspecific image, NS, is consistent with (18)F-flortaucipir images observed in Ab2 healthy controls, from whom tau is absent, demonstrating a homogeneous signal throughout the brain apart from increased uptake in the striatum consistent with known off-target binding of the tracer, which has been linked to monoami…”
Ricci, M., Cimini, A., Camedda, R., Chiaravalloti, A., & Schillaci, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313002 · Cited by 24 · see citing works
“Even if Tauvid imaging is useful when comparing PSP and PD patients [96], there is a substantial overlap of signals in multiple brain regions when comparing PSP patients with AD patients and healthy subjects [97].”
ResultDistinct [18F]THK5351 binding patterns in primary progressive aphasia variants
Schaeverbeke, J., Evenepoel, C., Declercq, L., Gabel, S., Meersmans, K., Bruffaerts, R., Adamczuk, K., Dries, E., Bouwel, K. V., Sieben, A., et al. (2018) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-018-4075-3 · Cited by 19 · see citing works
“[(18)F]AV1451 also binds to MAO-A [53], and this could also be the case for [(18)F]THK5351.”
BackgroundInfluentialSchaeverbeke, J., Celen, S., Cornelis, J., Ronisz, A., Serdons, K., van Laere, K., Thal, D., Tousseyn, T., Bormans, G., & Vandenberghe, R. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04631-x · Cited by 18 · see citing works
“The [(3)H]AV1451 binding affinity for MAO was comparable to its affinities for aggregated tau [24] and as such could lead to a confounding signal in PET studies.”
BackgroundResultInfluential[18F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment
Jeong, H.-J., Lee, H., Lee, S., Seo, S., Park, K. H., Lee, Y., Shin, D. J., Kang, J. M., Yeon, B. K., Kang, S., et al. (2020) · Journal of Clinical Neurology · doi:10.3988/jcn.2020.16.2.202 · Cited by 20 · see citing works
“72 These reports have indicated that about one-third of the [ 18 F]THK5351 cortical signal might not be attributable to tau.”
18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome.
Goodheart, A., Locascio, J., Samore, W. R., Collins, J. A., Brickhouse, M., Schultz, A., Touroutoglou, A., Johnson, K. A., Frosch, M., Growdon, J., et al. (2020) · Brain : a journal of neurology · doi:10.1093/brain/awaa383 · Cited by 17 · see citing works
PET and SPECT imaging of the brain: a review on the current status of nuclear medicine in Japan
Kaneta, T. (2020) · Japanese Journal of Radiology · doi:10.1007/s11604-019-00901-8 · Cited by 17 · see citing works
Advance and Prospect of Positron Emission Tomography in Alzheimer’s disease research
Wang, Y.-L., Liao, W.-C., Wang, L., Li, J., Huang, D.-Q., Cheng, W., Tian, J.-Z., & Luan, P. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03081-2 · Cited by 16 · see citing works
Satoh, R., Ali, F., Botha, H., Lowe, V., Josephs, K., & Whitwell, J. (2024) · NeuroImage · doi:10.1016/j.neuroimage.2024.120509 · Cited by 16 · see citing works
“In addition, the subcortical structures largely coincide with regions of abundant iron and monoamine oxidase, which may cause off-target binding of flortaucipir (Lowe et al., 2016; Vermeiren et al., 2018).”
The Role of Tau Imaging in Parkinsonian Disorders
Hammes, J., Drzezga, A., & van Eimeren, T. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0898-3 · Cited by 16 · see citing works
Cho, H., Seo, S., Choi, J., Lee, H. S., Ryu, Y., Lee, M., Na, D., Kim, H., & Lyoo, C. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.02.015 · Cited by 16 · see citing works
PET Neuroimaging in Dementia Conditions
Perani, D., Caminiti, S. P., Carli, G., & Tondo, G. (2020) · Springer eBooks · doi:10.1007/978-3-030-53168-3_9 · Cited by 20 · see citing works
A closer look at amyloid ligands, and what they tell us about protein aggregates.
Chisholm, T., & Hunter, C. A. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00518f · Cited by 15 · see citing works
Tracer development for PET imaging of proteinopathies
Kallinen, A., & Kassiou, M. (2022) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2022.04.001 · Cited by 18 · see citing works
Neuronal PET tracers for Alzheimer's disease.
Kumar, A. P., Singh, N., Nair, D. R., & Justin, A. (2021) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2021.11.093 · Cited by 15 · see citing works
Respondek, G., Levin, J., & Höglinger, G. (2018) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000581 · Cited by 15 · see citing works
Aliaga, A., Therriault, J., Quispialaya, K., Aliaga, A., Hopewell, R., Rahmouni, N., Macedo, A., Kunach, P., Soucy, J., Massarweh, G., et al. (2024) · Journal of Nuclear Medicine · doi:10.2967/jnumed.124.267539 · Cited by 14 · see citing works
Gatto, R. G., Carlos, A., Reichard, R., Lowe, V., Whitwell, J., & Josephs, K. (2023) · PLoS ONE · doi:10.1371/journal.pone.0284182 · Cited by 14 · see citing works
Campese, N., Palermo, G., Gamba, C. D., Beatino, M. F., Galgani, A., Belli, E., Prete, E. D., Vecchia, A. D., Vergallo, A., Siciliano, G., et al. (2021) · Expert Review of Proteomics · doi:10.1080/14789450.2021.1886929 · Cited by 23 · see citing works
Leinonen, V., Rauramaa, T., Johansson, J., Bottelbergs, A., Tesseur, I., van der Ark, P. D., Pemberton, D., Koivisto, A., Jääskeläinen, J., Hiltunen, M., et al. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-180071 · Cited by 14 · see citing works
Bisi, N., Pinzi, L., Rastelli, G., & Tonali, N. (2024) · Molecules · doi:10.3390/molecules29030722 · Cited by 13 · see citing works
“Among them, [ 125 I]IDP-4 (Figure 4) displayed the highest affinity for α Syn aggregates at K d values of 5.4 ± 1.5 nM with a 3-fold selectivity versus A β aggregates.”
BackgroundMethodResultInfluentialMonoamine oxidase binding not expected to significantly affect [18F]flortaucipir PET interpretation
Wright, J. P., Goodman, J. R., Lin, Y., Lieberman, B. P., Clemens, J., Gomez, L. F., Liang, Q., Hoye, A. T., Pontecorvo, M. J., & Conway, K. A. (2022) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-022-05822-9 · Cited by 13 · see citing works
“used excess non-radioactive flortaucipir to define nonspecific binding [20], whereas we chose control microsomes devoid of recombinant MAO-B.”
MethodLiu, T., Li, Y.-Y., Zhang, X.-J., Yao, A., Wang, Y., Yao, S., Chen, B., Yan, X.-X., Dai, J.-P., Zhang, J.-M., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00239 · Cited by 12 · see citing works
Mohamed, A. Z., Cumming, P., Nasrallah, F., & initiative, A. D. N. (2022) · Brain Science · doi:10.3390/brainsci12070876 · Cited by 12 · see citing works
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Tau Tangles in Parkinson’s Disease: A 2-Year Follow-Up Flortaucipir PET Study
Hansen, A. K., Parbo, P., Ismail, R., Østergaard, K., Brooks, D. J., & Borghammer, P. (2019) · Journal of Parkinson s Disease · doi:10.3233/jpd-191774 · Cited by 15 · see citing works
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“Previous studies suggested that off-target binding of [ 18 F]Flortaucipir (first generation tau-PET tracer) may be due to its affinity for monoamine oxidase B (MAO-B) and neuromelanin[6, 16].”
Chen, Y.-H., Joie, R. L., Pereira, F., Blazhenets, G., Zhu, L., Spina, S., Seeley, W., Heinsen, H., Ushizima, D., Tosun, D., et al. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-02983-x · Cited by 9 · see citing works
“Monoamine oxidase B (MAO-B), a known source of off-target signal for other first-generation tau PET tracers such as [18F]-THK5351 [2, 24, 40], has also been proposed as a potential contributor to off-target Flortaucipir signal (Baker, Harrison et al.).”
Thiophene-Based Optical Ligands That Selectively Detect Aβ Pathology in Alzheimer’s Disease
Klingstedt, T., Shirani, H., Ghetti, B., Vidal, R., & Nilsson, K. P. (2021) · ChemBioChem · doi:10.1002/cbic.202100199 · Cited by 9 · see citing works
Coevolution of Atomic Resolution and Whole-Brain Imaging for Tau Neurofibrillary Tangles
Dalton, R. M., Krishnan, H. S., Parker, V. S., Catanese, M. C., & Hooker, J. M. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00426 · Cited by 10 · see citing works
AD molecular: Imaging tau aggregates with positron emissions tomography
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Wolters, E. E., Ossenkoppele, R., Golla, S. S. V., Verfaillie, S. C. J., Timmers, T., Visser, D., Tuncel, H., Coomans, E. M., Windhorst, A. D., Scheltens, P., et al. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.102113 · Cited by 9 · see citing works
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“Flortaucipir has also shown in vitro affinity toward MAO-A and B [3].”
BackgroundYokoyama, Y., Harada, R., Kudo, K., Iwata, R., Kudo, Y., Okamura, N., & Furumoto, S. (2024) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2024.108986 · Cited by 7 · see citing works
Li, S., & Bhalla, R. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04178-w · Cited by 7 · see citing works
“T807 was reported to bind to both MAO-A and MAO-B alike [83], and also unlike THK5351, experiments conducted on rodent models demonstrated that MAO-B inhibitors including lazabemide and moclobemide could not block T807’s standardised uptake value (SUV) while deprenyl can successfully reduce its SUV…”
BackgroundResult
- Authors
- Vermeiren, C., Motte, P., Viot, D., Mairet‐Coello, G., Courade, J., Citron, M., Mercier, J., Hannestad, J., & Gillard, M.
- Affiliations
- UCB Pharma (Belgium) (BE)
- UCB BioPharma sprl, Chemin du Foriest Braine l'Alleud Belgium
- Denali Therapeutics (United States) (US)
- Corresponding author
- Vermeiren, Céline
- Venue
- Movement Disorders
- Publisher
- Wiley
- Published
- 2017-12-26
- Volume
- 33
- Issue
- 2
- Pages
- 273-281
- ISSN
- 0885-3185 (ISSN-L)
- 1531-8257
- OpenAlex
- W2779391140
- Cited by
- 143
- References
- 0
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 15 · 2022: 14 · 2021: 17 · 2020: 26 · 2019: 28 · 2018: 17
- FWCI
- 14.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Movement Disorders (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- tau PET tracers, off-target binding, monoamine oxidase, monoamine oxidase A, monoamine oxidase B, tau fibrils, progressive supranuclear palsy, Alzheimer's disease, postmortem brain
- MeSH terms
- Alzheimer Disease, Animals, Brain, Carbolines, Contrast Media, Dose-Response Relationship, Drug, Humans, Monoamine Oxidase, Protein Binding, Radioligand Assay, Supranuclear Palsy, Progressive, Tritium, tau Proteins, Rats, Sprague-Dawley, Positron-Emission Tomography, Rats
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