Evaluation of [18F]MK-6240 binding to tau protein in postmortem human brains of Down syndrome and Alzheimer’s disease and assessment of off-target (non-tau) binding

Alzheimer's disease (AD) and Down Syndrome (DS) are characterized by the aggregation of tau tangles. As a novel tau PET tracer in AD, [ ¹⁸ F]MK-6240 has the potential in DSAD to elucidate pathophysiology and advance diagnostic strategies. Autoradiography of frontal cortex (FCX) and temporal cortex (TCX) postmortem brain slices of DSAD (n = 5), AD (n = 5), and cognitively normal (CN) (n = 5) cases indicated similarly high [ ¹⁸ F]MK-6240 binding in DSAD and AD cases. Anti-tau immunostains confirmed total tau presence so there was alignment in anti-tau abundance with quantification of [ ¹⁸ F]MK-6240 binding. DSAD and AD cases exhibited higher gray matter (GM)/white matter (WM) ratios of 2.8 and 2.5 respectively. For drug effects on [ ¹⁸ F]MK-6240 binding, self-displacement of [ ¹⁸ F]MK-6240 was by 88% among DSAD cases and 85% among AD cases while IPPI displaced [ ¹⁸ F]MK-6240 by 81% and 74% in DSAD and AD cases respectively. KuFal194, a specific phosphokinase inhibitor, minimally displaced [ ¹⁸ F]MK-6240 binding. Harmine competed with [ ¹⁸ F]MK-6240 with an IC ₅₀ value of 290 ± 218 nM and 92 ± 15 nM for DSAD and AD cases, respectively, suggesting unique tau binding. High meninges off-target (non-tau) binding of [ ¹⁸ F]MK-6240 was observed in a CN case, comparable to the GM in DSAD and AD. MK-6240 (10 µM) blocked 44% and T807 (10 µM) blocked 30% of meninges binding. Incubation of meninges in the presence of 0.2% polyethylenimine reduced 70% of [ ¹⁸ F]MK-6240 binding. The tau imaging agent, [ ¹²⁵ I]IPPI, an analog of [ ¹⁸ F]MK-6240, exhibited minimal binding to CN meninges. Our findings suggest [ ¹⁸ F]MK-6240 to be selective tau imaging agent in DSAD and AD, harmine to be a weak tau drug, and off-target nonspecific meninges binding maybe due to the primary aromatic amine group in [ ¹⁸ F]MK-6240.