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P1‐246: Discovery and First‐in‐Human Evaluation of the TAU‐Imaging PET Radiotracer [ 18 F]MK‐6240
Author(s) -
Bennacef Idriss,
Zeng Zhizhen,
Lohith Talakad,
Miller Patricia J.,
Salinas Cristian A.,
Connolly Brett M.,
Gantert Liza T.,
Haley Hyking D.,
Marie Holahan A.,
O’Malley Stacey S.,
Purcell Mona L.,
Riffel Kerry,
Coleman Paul J.,
Li Jing,
Balsells-Padros Jaume,
Soriano Aileen,
Ogawa Aimie M.,
Xu Serena,
Xiaoping Zhang,
Della Rocca Joseph,
Schachter Joel B.,
Hesk David,
David Schenk J.,
Telan-Choing Florestina,
Struyk Arie,
Sur Cyrille,
Celen Sofie,
Serdons Kim,
Bormans Guy,
Vandenbulcke Mathieu,
Vandenberghe Rik,
De Hoon Jan,
Koole Michel,
Van Laere Koen,
Declercq Ruben,
Tom Reynders,
Abbas Walji,
Eric Hostetler D.,
Evelhoch Jeffrey
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.995
Subject(s) - radioligand , positron emission tomography , human brain , in vivo , binding potential , nuclear medicine , pet imaging , white matter , pittsburgh compound b , chemistry , dementia , pathology , medicine , in vitro , neuroscience , biology , magnetic resonance imaging , biochemistry , disease , radiology , microbiology and biotechnology
bodies made against amyloid plaque (6E10) and NFTs (PHF6 & AT8) with brain slices adjacent to those of ARG study. Results: In AD brain slices, [H]MK-6240 binds AD tauopathy brain regions showing abundant NFTs. [H]MK-6240 binding is inhibited by self-block and T-808, but not by PIB. [H]MK-6240 binding patterns in NFT-rich AD brain slices are similar to IHC stain patterns of NFTs from the adjacent tissue slices. In non-AD brain slices, [H]MK-6240 exhibits minimal binding while [H]AV-1451 displays dense displaceable binding in the gray matter of cortex and hippocampus by self-block, but not by T-808. In tissue homogenate binding assays, [H]MK-6240 shows great binding potential (Bmax/Kd 1⁄4 226) in NFT-rich AD brain cortex by selfblock. [H]MK-6240 binds to one site with high affinity (Kd 1⁄4 0.286 0.09 nM). In non-AD brain cortex, [H]MK-6240 displays minimal non-saturable binding. In contrast, [H]-AV-1451 binds to more than one site in AD brain and shows displaceable binding in non-AD brain. Clorgyline inhibits [H]AV-1451 but not MK6240 binding in non-AD brain cortex (Ki1⁄4 0.43 nM). Conclusions: The study demonstrates [H]MK-6240 is a selective tau PET tracer with great binding potential and minimal non-specific binding in human AD brains. The data supports further development of MK-6240 as a tau-selective PET tracer.