title: cGMP production of the radiopharmaceutical [18F]MK-6240 for PET imaging of human neurofibrillary tangles.
abstract: Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [18F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FXFN. Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [18F]fluoride (K[18F]/K222) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170-250 mCi) of [18F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [18F]fluoride) with a specific activity of 222 ± 67 GBq/μmol (6.0 ± 1.8 Ci/μmol) at the end of synthesis (90 minutes; n = 3). [18F]MK-6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.|Department of Radiology, Harvard Medical School, Boston, MA, USA.|Advion Inc., Ithaca, NY, USA.
authors.forename: Thomas Lee
authors.initials: TL
authors.lastname: Collier
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.|Department of Radiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Yokell
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.|Department of Radiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Livni
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O&N 2, KU Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.affiliation: Department of Nuclear Medicine, UZ Leuven, Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Serdons
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.|Department of Radiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Neelamegam
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O&N 2, KU Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.affiliation: Merck Research Laboratories, Merck & Co., West Point, PA, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Harris
authors.affiliation: Merck Research Laboratories, Merck & Co., West Point, PA, USA.
authors.forename: Abbas
authors.initials: A
authors.lastname: Walji
authors.affiliation: Merck Research Laboratories, Merck & Co., West Point, PA, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: Merck Research Laboratories, Merck & Co., West Point, PA, USA.
authors.forename: Idriss
authors.initials: I
authors.lastname: Bennacef
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA.|Department of Radiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Neil
authors.identifier: 0000-0002-2087-5125
authors.initials: N
authors.lastname: Vasdev
mesh_terms: D005462:Fluorine Radioisotopes; D054879:Halogenation; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011786:Quality Control; D011854:Radiochemistry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D005462:Fluorine Radioisotopes; D007546:Isoquinolines; C000618291:MK-6240; D019275:Radiopharmaceuticals; C000615276:Fluorine-18
keywords: Alzheimer's disease; MK-6240; PET; TRACERlab FX-FN; fluorine-18; tau