Method for stabilizing non carrier added 2-[18F]fluoromethyl-l-phenylalanine, a new tumour tracer, during radiosynthesis and radiopharmaceutical formulation

IntroductionNon carrier added (NCA) 2-[18F]fluoromethyl-l-phenylalanine is currently used in a Phase I study. Improvement of the stability of the fluorobenzyl analogue, very sensitive to defluorination and hydrolysis, during the synthetic route and in the radiopharmaceutical formulation was devised.MethodsThe protected brominated precursor was synthesised in three steps. The labelling with [18F−] occurred in acetonitrile using K2CO3/K2.2.2 (120°C, 5 min). NCA 3-(2-[18F−]Fluoromethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid tert-butyl ester recovered from HPLC was submitted to deprotection in TFA/CH2Cl2 in the presence of CaCl2. After evaporation and adsorption on a mini C18 column, the tracer was recovered in 4 ml of H2O. Appropriate amounts of CaCl2 and NaCl solutions were added for isotonic formulation, and this solution was sterilised by a 0.2-μm Cathivex filter. Shelf-life stability in the presence of Ca2+ and Mg2+ ions was studied. Stereoisomeric purity was checked by chiral HPLC.ResultsThe labelling showed a reproducible labelling yield of at least 90%. The followed strategy and the presence of Ca2+ ions during deprotection, minimizing the loss of [18F−] from the labile fluorobenzyl group, allowed to obtain a decay-corrected yield of 75%. No racemisation was observed. The radiopharmaceutical formulation containing 0.04 M CaCl2 allows a shelf-life of about 6 h without significant radiodefluorination.ConclusionThe described synthetic route yields 40% of radiochemical pure NCA 2-[18F]fluoromethyl-l-phenylalanine within 105 min. A solution was found to reduce considerably the radiodefluorination. Addition of CaCl2 prior to deprotection limits the loss of radiofluoride to less than 10%. The calcium ions present in the final radiopharmaceutical formulation (0.04 M) assure a shelf-life of at least 6 h.