title: Optimization of nucleophilic ¹⁸F radiofluorinations using a microfluidic reaction approach.
abstract: Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical (18)F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5-10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [(18)F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [(18)F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Giancarlo
authors: G
authors: Pascali
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Lidia
authors: L
authors: Matesic
authors: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Thomas L
authors: TL
authors: Collier
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Naomi
authors: N
authors: Wyatt
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Benjamin H
authors: BH
authors: Fraser
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Tien Q
authors: TQ
authors: Pham
authors: Institute of Clinical Physiology, National Research Council, Pisa, Italy.
authors: Piero A
authors: PA
authors: Salvadori
authors: LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia.
authors: Ivan
authors: I
authors: Greguric
mesh_terms: D002623:Chemistry Techniques, Analytical / Q000379:methods*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods*; D044085:Microfluidics / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals