title: Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A.
abstract: Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[18F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([18F]AQ28A). [18F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[18F]F-K2.2.2-carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [18F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol-1) for further evaluation. Initially, we investigated the binding of [18F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [18F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [18F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Sally
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.affiliation: BioCrea GmbH, Radebeul, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.affiliation: BioCrea GmbH, Radebeul, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hoefgen
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008024:Ligands; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014018:Tissue Distribution
chemical_list: C000625385:AQ28A compound; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D008024:Ligands; D011810:Quinoxalines; D019275:Radiopharmaceuticals; D010727:Phosphoric Diester Hydrolases
keywords: 18F-labeled radioligand; PDE10 radioligand; animal PET/MR; automated synthesis; bromo precursor; nitro precursor