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.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

“…The radiosynthesis was then attempted using the commerical microfluidic system38; however, complete HPLC separation of the nitro precursor from the final product proved to be problematic (Supplementary Figs 16 and 17). Given that precursor ( R )-4 or ( R )-5 possesses an electron-rich aromatic ring and are only mildly activated towards nucleophilic aromatic substitution reactions due to the presence of the para -amide, it represents a challenging substrate for labelling with fluorine-18 using conventional labelling methods.…”

“…To this end, radiosynthesis of ( R )-1 was repeated and the reaction parameters optimized using a commercial microfluidic system and following the optimization procedure. The radiosynthesis was then attempted using the Discovery mode of the Advion NanoTek microfluidic system38, and the optimal conditions were determined to be ∼14 mg ml −1 (3 mg) of the nitro precursor ( R )-4 in DMSO (200 μl), a 100 μm × 2 m reactor at a temperature of 220 °C, with a flow rate of 40 μl min −1 . To ensure complete deprotection of all labelled materials, the product was hydrolysed using 1 ml of ethanolic HCl, at 100 °C for 3 min; however, complete HPLC separation of the nitro precursor from the final product proved to be problematic.…”

Synthesis of 18F-arenes from spirocyclic iodonium(III) ylides via continuous-flow microfluidics

“…A commercial continuous-flow microfluidic platform (NanoTek ® ; Advion, Inc.) [12] was utilised for this study. A model biphenyl iodonium ylide precursor was explored for initial proof-of-concept and reaction optimisation using tetraethylammonium [ 18 F]fluoride ([ 18 F]TEAF) as the 18 F-fluoride source, formed by the elution of 18 F-fluoride from an anion exchange cartridge with a solution of tetraethylammonium bicarbonate (TEAB).…”

Synthesis, bioconjugation and stability studies of [18F]ethenesulfonyl fluoride

“…17 Precursor solution and [ 18 F]fluoride complexes were pre-loaded onto two separate storage loops, and were delivered (10-20 μL for optimisation, 100-200 μL for production) at a set rate into a microreactor (2 m × 100 μm, 15.6 μL, fused silica) heated at predetermined temperatures. 17 Precursor solution and [ 18 F]fluoride complexes were pre-loaded onto two separate storage loops, and were delivered (10-20 μL for optimisation, 100-200 μL for production) at a set rate into a microreactor (2 m × 100 μm, 15.6 μL, fused silica) heated at predetermined temperatures.…”