title: Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles.
abstract: 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 tracer18F-MK-6240.
  
  
  METHODS
  In vitro binding studies were conducted with3H-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 with3H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with18F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain.18F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo.
  
  
  RESULTS
  The3H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices.3H-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.3H-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,18F-MK-6240 displayed rapid and homogeneous distribution in the brain. The18F-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.
  
  
  CONCLUSIONS
  18F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients.
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania eric.hostetler@merck.com.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Abbas M
authors.initials: AM
authors.lastname: Walji
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miller
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Idriss
authors.initials: I
authors.lastname: Bennacef
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Hyking
authors.initials: H
authors.lastname: Haley
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Talakad G
authors.initials: TG
authors.lastname: Lohith
authors.affiliation: Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Paul
authors.initials: P
authors.lastname: Coleman
authors.affiliation: Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Aimie
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Serena
authors.initials: S
authors.lastname: Xu
authors.affiliation: Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Drug Metabolism, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joshi
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Della Rocca
authors.affiliation: Labelled Compound Synthesis, Merck & Co., Inc., Rahway, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.affiliation: Labelled Compound Synthesis, Merck & Co., Inc., Rahway, New Jersey.
authors.forename: David J
authors.initials: DJ
authors.lastname: Schenk
authors.affiliation: Translational Biomarkers, Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D016874:Neurofibrillary Tangles; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry
chemical_list: D007546:Isoquinolines; C000618291:MK-6240; D011849:Radioactive Tracers
keywords: 18F; Alzheimer’s disease; PET; neurofibrillary tangles; tau