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

摘要

INTRODUCTION: Non carrier added (NCA) 2-[(18)F]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. METHODS: The protected brominated precursor was synthesised in three steps. The labelling with [(18)F(-)] occurred in acetonitrile using K(2)CO(3)/K(2.2.2) (120 degrees C, 5 min). NCA 3-(2-[(18)F(-)]Fluoromethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid tert-butyl ester recovered from HPLC was submitted to deprotection in TFA/CH(2)Cl(2) in the presence of CaCl(2). After evaporation and adsorption on a mini C18 column, the tracer was recovered in 4 ml of H(2)O. Appropriate amounts of CaCl(2) and NaCl solutions were added for isotonic formulation, and this solution was sterilised by a 0.2-microm Cathivex filter. Shelf-life stability in the presence of Ca(2+) and Mg(2+) ions was studied. Stereoisomeric purity was checked by chiral HPLC. RESULTS: The labelling showed a reproducible labelling yield of at least 90%. The followed strategy and the presence of Ca(2+) ions during deprotection, minimizing the loss of [(18)F(-)] 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 CaCl(2) allows a shelf-life of about 6 h without significant radiodefluorination. CONCLUSION: The described synthetic route yields 40% of radiochemical pure NCA 2-[(18)F]fluoromethyl-l-phenylalanine within 105 min. A solution was found to reduce considerably the radiodefluorination. Addition of CaCl(2) 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.