Student: Fraser Edgar
1st supervisor: Phil Miller, Imperial College London
2nd supervisor: Tony Gee, King’s College London
The aim of this project is to develop the concept of near-stoichiometric C-11 radiolabeling using a droplet based microfluidic reactor that will enable the rapid synthesis and purification of PET tracers.
Key objectives:
- to develop a microfluidic platform for efficiently trapping volatile and reactive C-11 precursors (for example CH3I, CO2, CS2, CO, etc.)
- controlled measurement and reaction of precursor nanolitre droplets with radiolabelled synthons
- manipulation of radiolabelled droplets on a microfluidic platform for further reaction, analysis and/or purification and formulation.
- application of this labelling platform to relevant tracer molecules (for the development of new C-11 tracers and for the production of existing ones)
Despite the apparent small scale of PET radiolabelling reactions, typically within volumes ranging from 100-500 µL, the quantities of solvent and precursors are far exceed (~103-106) that of the radioisotope. This causes several key problems for high specific activity radiolabelling processes, these include: slow reaction rates (a result of such dilute radioisotopic solutions), the need to add excess cold precursors in order to improve reaction rates and the need to separate excesses of unreacted cold precursors and solvents post reaction. ‘Near-stoichiometric’ labelling reactions, whereby amounts of cold reagents and solvents are much lower than conventional labelling reactions, are an attractive route for PET labelling reactions because they would avoid the vast excesses of cold reagents, improve reaction kinetics and simplify purification procedures. However, to achieve such near-stoichiometric labelling reactions two key requirements need to be met: (i) an ~105 fold reduction in the amount of solvent used to dilute the radioactive precursor, giving concentrations on the order of 0.01M for viable reaction kinetics (ii) an extremely accurate way of measuring the small quantities of cold reagents required for such reactions, typically ~0.1-1 µg. By exploiting microfluidics, this project will achieve these two key requirements and thus lead to anticipated improvements in the labelling efficiency, purification, processing and formulation of PET tracers.
Although the advantages of microfluidics – small size, easy shielding and automation, rapid mixing and heat transfer – for radiolabelling have been recognised for some time, significant improvements in labelling reactions (radiochemical yields and purities) have not been made because most reactions are performed in a ‘flow system’ where reagents are pumped through a microchannel reactor. Under such flow processes, radioisotope solution concentrations are still dilute and present no significant advantage in reducing volumes or precursor concentrations. The recent development of nano and microdroplet generators is currently revolutionising high throughput chemical, biological and analytical techniques, with the potential to perform, process and analyse reactions on the nanomole scale. By applying the principle of nanoscale reactions to radiolabelling it should be possible to greatly reduce total reaction volumes of solvent and excessive quantities of cold reagents, and thus improve the overall efficiency of labelling reactions.
The basic design of the microfluidic reactor to achieve this is conceptually straightforward (see figure below in section 4) and it will perform the key steps of freeze trapping C-11 synthons, measuring a nanolitre volumes of cold precursors and reacting/processing the droplet reactions for collection and formulation, or for further reaction and/or analysis. The reactor will be tested initially for C-11 methyl iodide reactions since this is the most common C-11 reagent with excellent physical properties for freeze trapping (mp. -67 ºC, bp. 42 ºC) and further reaction, however, once the method is establish it is possible to envisage the application to other volatile and reactive C-11 synthons for the preparation of known and novel tracers.