Brain Imaging of Alzheimer Dementia Patients and Elderly Controls with ¹⁸F-MK-6240, a PET Tracer Targeting Neurofibrillary Tangles

Abstract

F-MK-6240 is a highly selective, subnanomolar-affinity Positron Emission Tomography (PET) tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of F-MK-6240 in healthy elderly subjects (HE), subjects with clinically probable Alzheimer disease (AD), and amnestic mild cognitive impairment (MCI) were characterized in a first-in-human study. Dynamic PET scans of up to 150 min were performed in 4 cognitively normal HE, 4 AD and 2 MCI subjects, after bolus injection of 152-169 MBq F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional standardized uptake value ratio (SUVR) and distribution volume ratio (DVR) were determined using the cerebellar cortex as a reference region. Total distribution volume () was assessed by compartmental modeling using radiometabolite corrected input function in a subgroup of 6 subjects. F-MK-6240 had rapid brain uptake with peak standardized uptake value of 3-5, followed by a uniformly quick washout from all brain regions in HE; slower clearance was observed in regions commonly associated with NFT deposition in AD. In AD, SUVR measured between 60-90 min postinjection was high (approximately 2-4) in regions associated with NFT deposition; whereas, in HE, SUVR was approximately 1 across all brain regions suggesting high tracer selectivity for binding NFTs in vivo.F-MK-6240 VT was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD compared with HE, and stabilized by 60 min in both groups. DVR estimated by Logan reference tissue model or compartmental modeling correlated well (R >0.9) to SUVR for AD. F-MK-6240 exhibited favorable kinetics with high-binding levels to brain regions with a plausible pattern for NFT deposition in AD. In comparison, negligible tracer binding was observed in HE. This pilot study suggests simplified ratio methods such as SUVR can be employed to quantify NFT binding. These results support further clinical development ofF-MK-6240 for potential application in longitudinal studies.

Imaging Protein Misfolding in the Brain Using β-Sheet Ligands

“…Preclinical binding analysis also has suggested lower binding affinity of these second-generation tracers to MAO-A and MAO-B, than the binding affinity of the first-generation tracers such as 18 F-AV1451 and 18 F-THK5351. A recent first-in-human study showed no detectable signal in the basal ganglia and brainstem, suggesting high binding selectivity of these tracers to tau deposition in patients with AD ( Villemagne, 2017 ; Lohith et al, 2018 ; Wong et al, 2018 ). Further validation studies are required to confirm the binding selectivity of these tracers.…”

Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

“…The limited in vivo data reported for other new-generation tau tracers showed similar results to our study: [ 18 F]-MK6240, [ 18 F]RO-948, and [ 18 F]-PI6260 showed elevated signals in temporal areas and more broadly throughout the cortex in AD patients compared to NC subjects. The SUVRs in temporal lobe of AD/MCI patients were 1.64 (±0.72) with [ 18 F]-MK6240 [MMSE = 18.8 (±6.9), Cohen d = 1.3) ( Lohith et al, 2019 ), 2.75 (±1.40) with [ 18 F]RO-948 (inferior temporal lobe, MMSE = 20.8 (±2.7), Cohen d = 1.6] ( Wong et al, 2018 ), and 1.80 (±0.40) with [ 18 F]-PI2620 [inferior temporal, MMSE = 20.4 (±6.3), Cohen d = 2.4] ( Mueller et al, 2019 ). Our findings of [ 18 F]-APN-1607 had relatively lower SUVR in the present study [temporal lobe: 1.64 (±0.50), MMSE = 17.0 (±7.6), Cohen d = 2.1] comparing to [ 18 F]RO-948 and [ 18 F]-PI2620, which might arise from the relatively rough ROI; however, the relatively high Cohen d value indicated that [ 18 F]-APN-1607 was a highly sensitive tracer for detecting tau aggregates in AD.…”

Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer’s disease cases

“…An in vitro study of the second-generation MK6240 tracer has shown a high binding affinity for brain homogenate rich in NFTs [21,24]. Similarly, a recent in vivo pilot study by Lohith et al in AD patients showed that MK6240 binding occurred in regions rich in NFT deposits [25]; More recently, Pascoal et al reported that 18 F-MK6240 could be used to differentiate early and late disease stages of AD as well as discriminating AD from cognitively unimpaired and frontotemporal dementia [26]. In silico modelling has suggested the possibility of four theoretical binding sites on tau fibrils for MK6240 [27].…”