Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles

Abstract

Purpose: 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's Disease (AD). The preclinical characterization of the tau PET tracer ¹⁸F-MK-6240 is described. Procedures: In vitro binding studies were conducted with ³H-MK-6240 in tissue slices and homogenates from cognitively normal and Alzheimer’s disease (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 ³H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with ¹⁸F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in brain. ¹⁸F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. Results: The ³H-MK-6240 binding pattern is consistent with the distribution of phosphorylated tau in human AD brain slices. ³H-MK-6240 binds with high affinity to human AD brain cortex homogenates containing abundant NFTs, but binds poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. ³H-MK-6240 shows 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, ¹⁸F-MK-6240 displays rapid and homogeneous distribution in the brain. The ¹⁸F-MK-6240 volume of distribution (VT) stabilizes rapidly, indicating favorable tracer kinetics. No displaceable binding is observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination is observed as skull uptake. Conclusion: ¹⁸F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients.