In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand 18F-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls

Abstract

Tau PET imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer disease (AD). This work investigates in vivo kinetics, quantification strategies, and imaging characteristics of a novel tau PET radioligand ¹⁸F-MK-6240 in humans. Methods: Fifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted MRI as well as ¹¹C-PiB and ¹⁸F-MK-6240 PET imaging. PET data were coregistered to the MRI, and time-activity curves were extracted from regions of interest to assess ¹⁸F-MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis [LGA] and multilinear reference tissue method [MRTM2]) were investigated for quantification of ¹⁸F-MK-6240 distribution volume ratios (DVRs) in a subset of 19 participants. Stability of DVR methods was evaluated using truncated scan durations. SUV ratio (SUVR) estimates were compared with DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature. Results: SUVs in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared with MRTM2. DVR estimates remained stable when truncating the scan duration to 60 min. SUVR determined 70-90 min after injection of ¹⁸F-MK-6240 indicated linearity near unity when compared with DVR estimates and minimized potential spill-in from uptake outside the brain. ¹⁸F-MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus. Conclusion:¹⁸F-MK-6240 is a promising PET radioligand for in vivo imaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

Keywords: Alzheimer’s disease; MK-6240; positron emission tomography; quantification; tau.

FIGURE 1.

¹⁸F-MK-6240 SUV time–activity curves of all 51 participants in the cerebellum (left) and the pons (right). No individuals had evidence of specific binding in either ROI.

FIGURE 2.

¹⁸F-MK-6240 target-to-cerebellum ratio time–activity curves for regions associated with tau pathology (left 2 columns) and regions with off-target binding (outlined right column) for all 51 participants. Red line indicates an SUVR = 1.

FIGURE 3.

Comparison of ¹⁸F-MK-6240 DVR estimates using MRTM2 and LGA (left) using full dynamic time series (90, 105, or 120 min), and LGA (middle) and MRTM2 (right) DVR estimates using shortened 60-min dynamic scans compared with their corresponding full dynamic estimates. Red lines indicate unity (slope = 1, intercept = 0).

FIGURE 4.

Comparison of SUVR with MRTM2 DVR for SUVR determined from 60 to 80 (left) and 70 to 90 (right) min after ¹⁸F-MK-6240 injection. Red line indicates unity.

FIGURE 5.

Mean parametric ¹⁸F-MK-6240 SUVR(70–90 min) images taken across controls (top, n = 29) and PiB(+) AD and MCI individuals (bottom, n = 6) in MNI template space demonstrating common off-target and on-target binding.

FIGURE 6.

¹⁸F-MK-6240 parametric SUVR(70–90 min) images in PiB(+) individuals organized by image-based Braak stages. ¹⁸F-MK-6240 spatial binding patterns in PiB(+) individuals recapitulated patterns consistent with neuropathological staging of AD, including in the hippocampus. The PiB(+) dementia patient in far-right column was clinically diagnosed with probable AD dementia (not informed by biomarkers), but exhibited only circumscribed ¹⁸F-MK-6240 signal in the entorhinal region. MoCA = Montreal Cognitive Assessment.