title: Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).
abstract: Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was 233.5 ± 177.8 GBq/μmol (n = 4). The radiochemical yield of [(18)F]3 was 16.4 ± 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, Massachusetts 02129, United States.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.forename: Pekka
authors.initials: P
authors.lastname: Poutiainen
authors.forename: Zhaoda
authors.initials: Z
authors.lastname: Zhang
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.forename: Ji-Kyung
authors.initials: JK
authors.lastname: Choi
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jokivarsi
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D016466:CHO Cells; D003412:Cricetulus; D005260:Female; D005462:Fluorine Radioisotopes; D008253:Macaca mulatta; D008297:Male; D010797:Phthalimides / Q000138:chemical synthesis*; D010848:Picolinic Acids / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; C000595655:N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide; D010797:Phthalimides; D010848:Picolinic Acids; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4