Batch-mode microfluidic radiosynthesis of N-succinimidyl-4-[F-18]fluorobenzoate for protein labelling

The batch microfluidic technology is a promising system for sequential chemical steps combining the advantages of micro-scale reactions, while addressing some shortcomings of flow-through systems. We report herein the convenient three-step, one-pot synthesis and purification of [ 18F]SFB. [ 18F]SFB is a radiolabelling agent that can be used to label sensitive biomolecules, which are not accessible by direct nucleophilic 18F-fluorination. Five sequential steps were performed with a batch microfluidic device to obtain the short-lived positron-emitter- labelled molecule. Aqueous [ 18F]fluoride was concentrated and further eluted to a microreactor for evaporation. Nucleophilic 18F- fluorination of the precursor was carried out at high temperature, prior to hydrolysis and subsequent activation of the 4-[ 18F]fluorobenzoyl group. Purification on miniaturized solid-phase finally afforded [ 18F]SFB in 25 min and 55±6% yield (not decay-corrected) and >98% radiochemical purity. In this study, microfluidic prepared [ 18F]SFB could be further successfully used for labelling the epidermal growth factor protein. These results illustrate how microfluidic batch devices are advantageous for producing radiotracers for molecular imaging, e.g. Positron emission tomography. The technology offers many benefits such as the possibility to use much smaller quantities of starting material, reduced reaction time combined with improved efficiency, and easier purification. Copyright © 2010 John Wiley and Sons, Ltd

Pre-clinical evaluation of a 3-nitro-1,2,4-triazole analogue of [18F]FMISO as hypoxia-selective tracer for PET.

Hypoxia in solid tumours is associated with the promotion of various metabolic mechanisms and induces resistance to radio- and chemotherapy. Non-invasive positron emission tomography (PET) or single photon emission computed tomography by use of selective biomarkers has emerged as valuable tools for the detection of hypoxic areas within tumours so treatment can be modified accordingly. The aim of this investigation was to evaluate [(18)F]3-NTR, a 3-nitro-1,2,4-triazole analogue (N(1) substituted) of [(18)F]FMISO as a potential hypoxia selective tracer. 3-NTR and its (18)F-radiolabelled isotopic isomer were synthesised and compared with FMISO in vitro and in vivo. Their physicochemical properties were measured, the enzymatic reduction was evaluated, and the reactivity of their metabolites was investigated. Biodistribution and PET scans were performed on CBA mice bearing hypoxic CaNT tumour cells, using (18)F-labelled versions of the tracers. [(18)F]3-NTR uptake within hypoxic cells was lower than [(18)F]FMISO and [(18)F]3-NTR did not exhibit any better selectivity than FMISO as a PET tracer in vivo. Both (18)F-radiolabelled compounds are relatively evenly distributed within the whole body and the radioactive uptake within hypoxic tumours reaches a maximum at 30 min post injection and decreases thereafter. Xanthine oxidase exhibited a nitroreductase activity toward 3-NTR under anaerobic conditions, but reduced metabolites did not bind covalently. It is confirmed that 3-NTR is an electron acceptor. It is postulated that radiolabelled metabolites and fragments of [(18)F]3-NTR are freely diffusing due to their poor binding capacities. Thus [(18)F]3-NTR cannot be used as a hypoxia selective tracer for PET. The investigation provides insights into the importance of the propensity to form covalent adducts for such biomarkers

Performing radiosynthesis in microvolumes to maximize molar activity of tracers for positron emission tomography

For many applications, positron emission tomography tracers must be produced with high specific activity. Here the authors identify variables leading to increased specific activity when tracers are synthesized in microliter volumes, and show that specific activity can influence tracer biodistribution