Abstract
1174
Objectives Radiofluoronated L-Amino acids are a promising class of tumor metabolic imaging agents for PET with successful clinical applications. Recently, the novel radio-fluorination method via copper-mediated aromatic nucleophilic substitution with aryl pinacol boronates was reported. The high specific activity and high radiochemical yield synthesis of 4-[18F]fluorophenylalanine (4-[18F]FPA) from aryl diazonium tetrafluoroborates precusor had been accomplished, but its biological application is still unclear. Here, we synthesized 4-[18F]FPA from phenylalanine pinacol boronates precusor with K18F via directed copper-mediated radio-fluorination and evaluated in comparison to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET).
Methods The 4-[18F]fluorophenylalanine (4-[18F]FPA) was successfully synthesized from phenylalanine boronic esters via a rapid and efficient two-step directed copper-mediated nucleophilic fluorination and deprotection reaction. In vitro studies were carried out in U87-MG glioma cells. In vivo studies, the U87-MG bearing tumor mice model were used.
Results The 4-[18F]-fluorophenylalanine were efficiently labeled with high radiochemically purity (>95%), high specific activity (> 8GBq/umol) and good radiochemical yield(RCY) 20 ± 5% at 5 mCi to 50 mCi scale. The cellular uptake studies showed [18F]FPA had higher uptake than [18F]FET in U87-MGcells line from increased rapidly and reached a steady-state level for first 5 min of incubation. In the cell transporter competitive inhibition study, the uptake mechanism suggested that [18F]FPA exhibited preference towards one subtype of system L, LAT1. The biodistribution study demonstrated [18F]FPA had specific accumulation in U87-MG tumor cell and tumor to muscle ratio reached 2.00 at 60 min that is closed to [18F]FET aggregation. Micro PET imaging studies showed [18F]FPA had high uptake in U87-MG tumor compared to surrounding tissue and was comparable to [18F]FET for imaging in U87-MG bearing mice model. Both of two tracers can be eliminated rapidly from the rental system.
Conclusions The advantages of the novel synthesis of 4-[18F]FPA, which relies on copper-mediated aromatic nucleophilic substitution of a phenylalanine boronic esters precursor, can be rapid and efficient via two-step reaction easier than the conventional electrophilic methodolgy. The Biological evaluations indicate that [18F]FPA is a promising and potential tracer of PET for imaging U87-MG brain tumor.