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Annals of Nuclear Medicine
Published in: Annals of Nuclear Medicine 6/2019

01-06-2019 | Melanoma | Original Article

Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site

Authors: Tetsuro Tago, Jun Toyohara, Ryuichi Harada, Shozo Furumoto, Nubuyuki Okamura, Yukitsuka Kudo, Junko Takahashi-Fujigasaki, Shigeo Murayama, Kenji Ishii

Published in: Annals of Nuclear Medicine | Issue 6/2019

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Abstract

Objective

Amyloid-β plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer’s disease. In recent years, marked progress has been made in Alzheimer’s disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands.

Methods

Autoradiographic studies of [18F]AV-1451 and [18F]THK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of [18F]AV-1451 and [18F]THK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against [18F]THK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding.

Results

Autoradiography demonstrated specific binding of the radioligands in the substantia nigra. [18F]AV-1451 and [18F]THK5351 exhibited saturable binding to melanoma cells ([18F]AV-1451: Kd = 669 ± 196 nM, Bmax = 622 ± 269 pmol/mg protein; [18F]THK5351: Kd = 441 ± 126 nM, Bmax = 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of [18F]THK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM).

Conclusions

These studies suggest that the binding properties of [18F]AV-1451 and [18F]THK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC.
Appendix
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Literature
1.
Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207–16.CrossRefPubMedPubMedCentral
2.
Zwan MD, Okamura N, Fodero-Tavoletti MT, Furumoto S, Masters CL, Rowe CC, et al. Voyage au bout de la nuit: a beta and tau imaging in dementias. Q J Nucl Med Mol Imaging. 2014;58(4):398–412.PubMed
3.
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.CrossRefPubMed
4.
5.
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42(3 Pt 1):631–9.CrossRefPubMed
6.
Giacobini E, Gold G. Alzheimer disease therapy–moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9(12):677–86.CrossRefPubMed
7.
Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis. 2013;34(2):457–68.CrossRefPubMed
8.
Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79(6):1094–108.CrossRefPubMed
9.
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 disease. J Nucl Med. 2016;57(2):208–14.CrossRefPubMed
10.
11.
Marquie M, Normandin MD, Vanderburg CR, Costantino IM, Bien EA, Rycyna LG, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78(5):787–800.CrossRefPubMedPubMedCentral
12.
Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, et al. Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. Alzheimers Res Ther. 2017;9(1):25.CrossRefPubMedPubMedCentral
13.
14.
Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain. 2007;130(Pt 6):1566–76.CrossRefPubMed
15.
Walji AM, Hostetler ED, Selnick H, Zeng Z, Miller P, Bennacef I, et al. Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): a positron emission tomography (PET) imaging agent for quantification of neurofibrillary tangles (NFTs). J Med Chem. 2016;59(10):4778–89.CrossRefPubMed
16.
Garg S, Kothari K, Thopate SR, Doke AK, Garg PK. Design, synthesis, and preliminary in vitro and in vivo evaluation of N-(2-diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]-DAFBA): a novel potential PET probe to image melanoma tumors. Bioconjug Chem. 2009;20(3):583–90.CrossRefPubMedPubMedCentral
17.
Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M, et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med. 2013;54(8):1420–7.CrossRefPubMed
18.
Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973;22(23):3099–108.CrossRefPubMed
19.
20.
Yoo BY, Oreland L, Persson A. Letter. Effects of formaldehyde and glutaraldehyde fixation on the monoamine oxidase activity in isolated rat liver mitochondria. J Histochem Cytochem. 1974;22(6):445–6.CrossRefPubMed
21.
Fidler IJ. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 1975;35(1):218–24.PubMed
22.
Hostetler ED, Walji AM, Zeng Z, Miller P, Bennacef I, Salinas C, et al. Preclinical characterization of 18F-MK-6240, a promising PET tracer for in vivo quantification of human neurofibrillary tangles. J Nucl Med. 2016;57(10):1599–606.CrossRefPubMed
23.
Tong J, Meyer JH, Furukawa Y, Boileau I, Chang LJ, Wilson AA, et al. Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies. J Cereb Blood Flow Metab. 2013;33(6):863–71.CrossRefPubMedPubMedCentral
24.
Hansen AK, Knudsen K, Lillethorup TP, Landau AM, Parbo P, Fedorova T, et al. In vivo imaging of neuromelanin in Parkinson’s disease using 18F-AV-1451 PET. Brain. 2016;139(Pt 7):2039–49.CrossRefPubMed
25.
Perez-Soriano A, Arena JE, Dinelle K, Miao Q, McKenzie J, Neilson N, et al. PBB3 imaging in Parkinsonian disorders: evidence for binding to tau and other proteins. Mov Disord. 2017;32(7):1016–24.CrossRefPubMed
26.
Betthauser TJ, Cody KA, Zammit MD, Murali D, Converse AK, Barnhart TE, et al. In vivo characterization and quantification of neurofibrillary tau PET radioligand [(18)F]MK-6240 in humans from Alzheimer’s disease dementia to young controls. J Nucl Med. 2018.
27.
Karlsson O, Lindquist NG. Melanin and neuromelanin binding of drugs and chemicals: toxicological implications. Arch Toxicol. 2016;90(8):1883–91.CrossRefPubMed
28.
Zecca L, Tampellini D, Gerlach M, Riederer P, Fariello RG, Sulzer D. Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Mol Pathol. 2001;54(6):414–8.PubMedPubMedCentral
29.
30.
Tanaka S, Yamamoto H, Takeuchi S, Takeuchi T. Melanization in albino mice transformed by introducing cloned mouse tyrosinase gene. Development. 1990;108(2):223–7.PubMed
31.
Lowe VJ, Curran G, Fang P, Liesinger AM, Josephs KA, Parisi JE, et al. An autoradiographic evaluation of AV-1451 Tau PET in dementia. Acta Neuropathol Commun. 2016;4(1):58.CrossRefPubMedPubMedCentral
32.
Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol. 1984;15(3):217–27.CrossRefPubMed
33.
Banay-Schwartz M, Kenessey A, DeGuzman T, Lajtha A, Palkovits M. Protein content of various regions of rat brain and adult and aging human brain. AGE. 1992;15(2):51–4.CrossRef
34.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–9.CrossRefPubMed
35.
Okamura N, Harada R, Furumoto S, Arai H, Yanai K, Kudo Y. Structure-binding relationship of quinoline derivatives on monoamine oxidase B. Hum Amyloid Imaging 2018; January 17–19, 2018; Miami2018.
36.
Harada R, Ishiki A, Kai H, Sato N, Furukawa K, Furumoto S, et al. Correlations of (18)F-THK5351 PET with postmortem burden of tau and astrogliosis in Alzheimer disease. J Nucl Med. 2018;59(4):671–4.CrossRefPubMed
37.
Double KL, Zecca L, Costi P, Mauer M, Griesinger C, Ito S, et al. Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins. J Neurochem. 2000;75(6):2583–9.CrossRefPubMed
38.
Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 2006;7(4):295–309.CrossRefPubMed
39.
Rimpela AK, Reinisalo M, Hellinen L, Grazhdankin E, Kidron H, Urtti A, et al. Implications of melanin binding in ocular drug delivery. Adv Drug Deliv Rev. 2018;126:23–43.CrossRefPubMed
40.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.CrossRefPubMed
41.
Uematsu M, Nakamura A, Ebashi M, Hirokawa K, Takahashi R, Uchihara T. Brainstem tau pathology in Alzheimer’s disease is characterized by increase of three repeat tau and independent of amyloid beta. Acta Neuropathol Commun. 2018;6(1):1.CrossRefPubMedPubMedCentral
42.
Jakubiak P, Reutlinger M, Mattei P, Schuler F, Urtti A, Alvarez-Sanchez R. Understanding molecular drivers of melanin binding to support rational design of small molecule ophthalmic drugs. J Med Chem. 2018;61(22):10106–15.CrossRefPubMed
43.
Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, et al. Structure–activity relationship of 2-arylquinolines as PET imaging tracers for tau pathology in Alzheimer disease. J Nucl Med. 2016;57(4):608–14.CrossRefPubMed
44.
Bungeler A, Hamisch B, Strube OI. The supramolecular buildup of eumelanin: structures, mechanisms, controllability. Int J Mol Sci. 2017;18(9).
Metadata
Title
Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site
Authors
Tetsuro Tago
Jun Toyohara
Ryuichi Harada
Shozo Furumoto
Nubuyuki Okamura
Yukitsuka Kudo
Junko Takahashi-Fujigasaki
Shigeo Murayama
Kenji Ishii
Publication date
01-06-2019
Publisher
Springer Singapore
Published in
Annals of Nuclear Medicine / Issue 6/2019
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-019-01344-x

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