In vivo quantification of neurofibrillary tangles with [18F]MK-6240

Abstract

BackgroundImaging agents capable of quantifying the brain’s tau aggregates will allow a more precise staging of Alzheimer’s disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [18F]MK-6240.MethodsIn vitro properties of [18F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging.ResultsIn vitro [18F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates.ConclusionsThis evaluation shows an [18F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.

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

“…Uptake was higher in AD subjects and was considerably higher in brain regions expected to have NFT like in the hippocampus, but very low uptake in the cerebellar gray matter suggests a potential use of the cerebellar gray matter as a reference region. Based on reliability analysis simplified quantitative approaches could offer informed estimates of NFT load [203]. Furthermore, the spatial patterns of binding of the tracer were in accordance with the neuropathological staging of NFT, as reported from recent clinical studies [204].…”

“…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].…”

Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

“…[ 18 F]AZD4694 images were acquired 40-70 minutes post-injection and scans were reconstructed with the OSEM algorithm on a 4D volume with 3 frames (3 x 600s). [ 18 F]MK6240 images were acquired 90-110 minutes post-injection and scans were reconstructed with the OSEM algorithm on a 4D volume with 4 frames (4 x 300s) 24 . Immediately following each PET acquisition, a 6minute transmission scan was conducted with a rotating 137 Cs point source for attenuation correction.…”

Neuroimaging in Dementias

“…Researchers have been striving to develop better tau radioligands to overcome these problems. Newer second generation tau tracers such as F-18 MK-6240, [69][70][71] F-18 PI-2620, and F-18 RO-948 72 all demonstrate highly specific binding to tau with favorable tracer kinetics and low off-target binding. These new tau PET biomarkers will play critical roles in advancing the understanding of tau pathology in AD and provide very useful tools for clinical trials of new therapies.…”