title: Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography.
abstract: Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2-4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. s.schroeder@hzdr.de.
authors.forename: Susann
authors.initials: S
authors.lastname: Schröder
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. b.wenzel@hzdr.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. w.deuther-conrad@hzdr.de.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. r.teodoro@hzdr.de.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.affiliation: BioCrea GmbH, Meissner Str. 191, Radebeul 01445, Germany. Ute.Egerland@biocrea.com.
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. m.kranz@hzdr.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. m.scheunemann@hzdr.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: BioCrea GmbH, Meissner Str. 191, Radebeul 01445, Germany. Norbert.Hoefgen@biocrea.com.
authors.forename: Norbert
authors.initials: N
authors.lastname: Höfgen
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. j.steinbach@hzdr.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany. p.brust@hzdr.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D051379:Mice; D059906:Neuroimaging / Q000379:methods*; D010539:Permeability; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D005462:Fluorine Radioisotopes; D010726:Phosphodiesterase Inhibitors; D019275:Radiopharmaceuticals; D014227:Triazines; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human
keywords: Alzheimer’s disease; PDE2A; PET imaging in brain; micellar HPLC