Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue

Abstract

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick’s disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

“…In autoradiography studies it also showed to tau aggregates/folds in PSP brain sections, which of course has been controversial, since many tau tracers has been reported not to be bind to tau deposits in PSP in autoradiography experiments. However, off-target binding was observed in the pars compacta portion of the substantia nigra in human brain sections, consistent with the affinity of some tau tracers like flortaucipir, [ 18 F]MK-6240 to melanin-containing cells [52,53,201].…”

“…Preclinical findings confirmed a lack of binding to MAO-A and MAO-B [203]. Unlike flortaucipir and [ 18 F]THK-5351 off-target binding was not seen in the choroid plexus and basal ganglia [204], but like flortaucipir and various tau PET tracers, off-target binding to neuromelanin-and melanin containing cells like the pigmented neurons in the substantia nigra, and meninges was observed [52,187,201]. To confirm initial observations, there are ongoing clinical trials on non-AD patients.…”

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

“…To address this, we preselected an atlas that excludes these typical AV1451 off-target binding regions. Still, it is possible, that unspecific AV1451 binding may influence our results, hence our findings await further replication once second-generation tau-PET tracers with a better off-target binding profile are available 41,42 . Here, it will be of special interest to study the role of the hippocampus in connectivity-related tau-spreading, which is a site of early tau pathology that may be critically involved in tau spread from alloto the neocortical regions 43,44 .…”

Development and evaluation of [125I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

“…This has resulted in overestimation of Tau. Recent in vitro studies with [ 18 F]MK‐6240 in AD brain suggests some displacement (up to 20% at high drug concentrations) and may not be a concern for in vivo PET studies (Aguero et al., 2019). Binding of [ 125 I]IPPI in brain slices containing AC and CC shown in Figure 8b correlated very well with the presence of Tau, confirmed by anti‐Tau Dako A0024 (Figure 8h).…”

“…As a NFT radiotracer, [ 18 F]MK‐6240 shows characteristic changes in the brains of patients with AD (Betthauser et al, 2019). More recently, using autoradiographic studies, [ 18 F]MK‐6240 has some propensity of being displaced by MAO inhibitors in vitro (Aguero et al., 2019).…”