Synthesis and Evaluation in Monkey of 18F4-Fluoro-N-methyl-N-(4-(6- (methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide (18FFIMX) a Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1)

摘要

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 [¹⁸F]>11 in useful radiochemical yield and in high specific activity from [¹⁸F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (>15). In baseline experiments in rhesus monkey, [¹⁸F]>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 a very high proportion of the radioactivity in monkey brain to be bound specifically and reversibly to mGluR1. [¹⁸F]>11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.