Selective synthesis of L‐2‐[18F]fluoro‐alpha‐methylphenylalanine via copper‐mediated 18F‐fluorination of (mesityl)(aryl)iodonium salt

L‐2‐[18F]fluoro‐alpha‐methylphenylalanine (2‐[18F]FAMP) is a promising amino acid tracer for positron emission tomography (PET) imaging, yet the low production yield of direct electrophilic radiofluorination with [18F]F2 necessitates further optimization of the radiolabeling process. This paper describes a two‐step preparation method for L‐2‐[18F]fluoro‐alpha‐methylphenylalanine (2‐[18F]FAMP) starting from [18F]fluoride. The (Mesityl)(L‐alpha‐methylphenylalanine)‐2‐iodonium tetrafluoroborate precursors with various protecting groups were prepared. The copper‐mediated 18F‐fluorination of the iodonium salt precursors successfully produced 2‐[18F]FAMP. The highest radio chemical conversion of 57.6% was noted with N‐Piv‐protected (mesityl)(aryl)iodonium salt in the presence of 5 equivalent of Cu (OTf)2. Subsequent deprotection with 57% hydrogen iodide produced 2‐[18F]FAMP within 120 min in 21.4 ± 11.7% overall radiochemical yield with >95% radiochemical purity and an enantiomeric excess >99%. The obtained 2‐[18F]FAMP showed comparable biodistribution profiles in normal mice with that of the carrier‐added 2‐[18F]FAMP. These results indicate that usefulness of copper mediated 18F‐fluorination for the production of 2‐[18F]FAMP, which would facilitate clinical translation of the promising tumor specific amino acid tracer. Individual facilities could adopt either production method based on radioactivity demand and equipment availability. The first radiosynthesis of 2‐[18F]FAMP from 18F‐fluoride. An alpha‐methyl group substantially affected the N‐protecting group selection. These findings potentially facilitate clinical applicability of 2‐[18F]FAMP.