Synthesis and Evaluation in Monkey of [18F]4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([18F]FIMX): A Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1)

Autor: Robert B. Innis, Alicia E. Woock, Victor W. Pike, Rong Xu, Sami S. Zoghbi, Paolo Zanotti-Fregonara, Robert L. Gladding
Rok vydání: 2013
Předmět:
Zdroj: Journal of Medicinal Chemistry. 56:9146-9155
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm4012017
Popis: 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.
Databáze: OpenAIRE