<p>Alzheimer's disease (AD) and Down Syndrome (DS) are characterized by the aggregation of tau tangles. As a novel tau PET tracer in AD, [¹⁸F]MK-6240 has the potential in Down syndrome-associated Alzheimer’s disease (DSAD) to elucidate pathophysiology and advance diagnostic strategies. Autoradiography of frontal cortex and temporal cortex postmortem brain slices of DSAD (n = 5), AD (n = 5), and cognitively normal (CN) (n = 5) cases indicated similarly high [¹⁸F]MK-6240 binding in DSAD and AD cases. [¹⁸F]MK-6240 binding in CN was substantially less than DSAD and AD. Anti-tau immunostains confirmed total tau presence that aligned with the localization of [¹⁸F]MK-6240 binding. DSAD and AD cases exhibited higher gray matter (GM)/white matter ratios of 2.8 and 2.5 respectively. For drug effects on [¹⁸F]MK-6240 binding, self-displacement by MK-6240 (10&#xa0;µM) reduced binding by 88% among DSAD cases and 85% among AD cases while IPPI (10&#xa0;µM) displaced [¹⁸F]MK-6240 by 81% and 74% in DSAD and AD cases respectively. KuFal194 (10&#xa0;µM), a specific phosphokinase inhibitor, minimally displaced [¹⁸F]MK-6240 binding. Harmine competed with [¹⁸F]MK-6240 with an IC₅₀ value of 290&#xa0;nM and 92&#xa0;nM for DSAD and AD cases, respectively. High meninges off-target (non-tau) binding of [¹⁸F]MK-6240 was observed in a CN case, comparable to the GM in DSAD and AD. MK-6240 (10&#xa0;µM) blocked 44% and T807 (10&#xa0;µM) blocked 30% of meninges binding. Incubation of meninges in the presence of 0.2% polyethyleneimine reduced 70% of [¹⁸F]MK-6240 binding. The tau radioligand, [¹²⁵I]IPPI, an analog of [¹⁸F]MK-6240, exhibited minimal binding to CN meninges compared to the DSAD and AD cases. Our findings suggest [¹⁸F]MK-6240 to be selective tau imaging agent in DSAD and AD, harmine to uniquely compete with [¹⁸F]MK-6240 binding in DSAD and provide preliminary insights to the off-target nonspecific binding of [¹⁸F]MK-6240 in postmortem meninges.</p>