(32b) The Synthesis of Isotopically Labelled Compounds in Micro Reactors

Radiolabelled molecules are of growing importance within the pharmaceutical and biomedical fields since they may be used within a diverse range of applications. For instance, radiolabelled isotopomers of drug candidates and significant metabolites are used in drug metabolism studies within the pharmaceutical industry, these would most commonly use [14C] but may alternatively use other isotopes, furthermore tritium labelled isotopomers are routinely used in mode of action studies. A second very topical application of radiochemistry is in positron emission tomography (PET) studies where molecules are labelled with positron-emitting isotopes, which possess very short half-lives, such as carbon-11 (11C, t1/2 = 20.3 min) and fluorine-18 (18F, t1/2 = 109.7 min). PET is an increasingly important medical imaging technique used for research and clinical applications in the detection of cancer, coronary artery disease and brain disease.

If we consider the present situation within a radioisotope group, the first synthesis would be the ?warm' radiosynthesis in which the reaction is spiked with a small amount of radioactivity in order to provide information on overall radioaccountability. Once this trial is successfully completed, a full radiosynthesis ('hot') is undertaken to provide radiolabelled product, which would be repeated as required. The downside of this approach is that the ?warm' reactions can never be considered as truly predictive of the undiluted ?hot' reaction, even if they are carried out on the same chemical scale. Thus, for a radiochemical synthesis the scale out of micro reactors to provide the required quantity would certainly be far less of an issue than that originally perceived with batch reactions. Hence a trial reaction using undiluted radiochemicals could be carried out effectively and safely in a single micro reactor with minimal sample quantity. It is envisaged that once a process has been successfully carried out within a micro reactor and scaled up to the required quantity using a parallel approach, then this customised system will be retained specifically for this reaction sequence. In this manner the reproducibility of the synthesis is guaranteed and the variability otherwise introduced by the work being carried out by different chemists is removed.

In this paper we report that micro reactors may be used to prepare labelled compounds by conducting all optimisation experiments using unlabelled precursors and simply substituting the labelled derivatives once the optimisation is complete. A range of reaction chemistries will be outlined including PET and stable isotope derivatives.