A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18 F-MK-6240. Methods: In vitro binding studies were conducted with 3 H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3 H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18 F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18 F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. Results: The 3 H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3 H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3 H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18 F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18 F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. Conclusion: 18 F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients. Cur rently, the clinical evaluation of disease-modifying therapies for Alzheimer disease (AD) requires large, resourceintensive clinical trials focused on measuring cognitive endpoints, which are highly variable. A biomarker that could be used early in clinical development to build confidence in the ability of a therapeutic mechanism to modify disease progression would provide a valuable bridge to investment in a large efficacy study once adequate pharmacokinetics, safety, and tolerability have been established. Biomarkers currently in use (e.g., volumetric MRI, amyloid plaque PET, cerebrospinal fluid measures of amyloid-b and tau) either do not directly inform on modification of disease pathology (volumetric MRI) or do not correlate strongly enough with cognitive decline to measure therapeutic response (amyloid plaque PET and cerebrospinal fluid measures) (1,2). Therefore, there is an unmet need for sensitive biomarkers that quantify early pathologic changes and correlate closely to disease progression and clinical outcomes.Histologic analysis of brains from human autopsy cases have shown that the density and distribution of neurofibrillary tangles (NFTs) correlate with cognitive decline ...