Abstract
PurposeMK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). The aim of the study was to characterize 3H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers.MethodsSaturation binding assays with 3H-MK6240 were carried out in the temporal and parietal cortices of AD brains to determine the maximum number of binding sites (Bmax) and the dissociation constants (Kd) at these sites. Competitive binding assays were carried out between 3H-MK6240 and unlabelled MK6240, AV-1451 (aka T807, flortaucipir) and THK5117, and between 3H-THK5351 and unlabelled MK6240. Regional binding studies with 3H-MK6240 were carried out in homogenates from six AD and seven control brains and, using autoradiography, on large frozen sections from two AD brains and one control brain.ResultsThe saturation binding assays gave Bmax and Kd values of 59.2 fmol/mg and 0.32 nM in the temporal cortex and 154.7 fmol/mg and 0.15 nM in the parietal cortex. The competitive binding assays revealed two binding sites with affinities in the picomolar and nanomolar range shared by 3H-MK6240 and all the tested unlabelled compounds. There were no binding sites in common between 3H-THK5351 and unlabelled MK6240. Regional binding of 3H-MK6240 was significantly higher in AD brain tissue than in controls. Binding in brain tissue from AD patients with early-onset AD was significantly higher than in brain tissue from patients with late-onset AD. Binding of 3H-MK6240 was not observed in off-target regions. Autoradiography showed high regional cortical binding in the two AD brains and very low binding in the control brain.Conclusions3H-MK6240 has a high binding affinity for tau deposits in AD brain tissue but also has different binding characteristics from those of the first-generation tau tracers. This confirms the complexity of tau tracer binding on tau deposits with different binding affinities for different binding sites.
Highlights
Alzheimer’s disease (AD) is characterized by the extracellular amyloid beta accumulation in the form of amyloid plaques and abnormal intracellular accumulation of tau protein into neurofibrillary tangles (NFTs) in the brain, both of which lead to progressive neurodegeneration [1]
We observed that 3H-MK6240 had a high binding affinity for tissue in the temporal cortices of two AD cases: Kd was 0.32 nM and Bmax was 59.2 fmol/mg
The difference in Bmax between the temporal cortex and the parietal cortex might have been the result of different brains being used in the experiment; disease progression was severe and fast for the EOAD patient
Summary
Alzheimer’s disease (AD) is characterized by the extracellular amyloid beta accumulation in the form of amyloid plaques and abnormal intracellular accumulation of tau protein into neurofibrillary tangles (NFTs) in the brain, both of which lead to progressive neurodegeneration [1]. Binding assays and competitive studies of first-generation tau PET tracers indicated that THK5117, THK5351 and AV-1451 targeted the same binding sites with different affinities, whereas PBB3 seemed to have its own target [9, 10]. First-generation tau PET tracers 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]. To avoid this scenario, a second generation of tau PET tracers has been designed; these include RO948, PI2620, JNJ311, MK6240, PM-PBB3 and AM-PBB3 [16]. In silico data have suggested that MK6240, JNJ311 and PI2620 have a low affinity for MAO-B [23]
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