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

22.02.2019 | Original Article

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

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

Erschienen in: Annals of Nuclear Medicine | Ausgabe 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.
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Metadaten
Titel
Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site
verfasst von
Tetsuro Tago
Jun Toyohara
Ryuichi Harada
Shozo Furumoto
Nubuyuki Okamura
Yukitsuka Kudo
Junko Takahashi-Fujigasaki
Shigeo Murayama
Kenji Ishii
Publikationsdatum
22.02.2019
Verlag
Springer Singapore
Erschienen in
Annals of Nuclear Medicine / Ausgabe 6/2019
Print ISSN: 0914-7187
Elektronische ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-019-01344-x

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