title: Synthesis and evaluation in monkey of [(18)F]4-fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([(18)F]FIMX): a promising radioligand for PET imaging of brain metabotropic glutamate receptor 1 (mGluR1).
abstract: We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [(18)F]11 in useful radiochemical yield and in high specific activity from [(18)F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [(18)F]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluR1. [(18)F]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Paolo
authors.initials: P
authors.lastname: Zanotti-Fregonara
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Woock
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C586005:4-fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide; D001549:Benzamides; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1