Concept and project objective(s)
The aim of this project is the design, fabrication and implementation of a micro device able to synthesise radiopharmaceuticals for Positron Emission Tomography (PET) analysis. In this diagnostic methodology, a drug with a known biological activity is labelled with a positron-emitting nuclide and injected into a patient; the in vivo imaging of the radioactivity allows monitoring several biological pathways, hence assessing the health of the patient undergoing the exam. The peculiarity of this technique, compared to other nuclear medicine approaches, is that the radiopharmaceutical has to be produced right before the tomographic exam due to the generally short half-life of the positron-emitting species (from minutes to few hours). This feature implies the requirement for quick, easy and reproducible radiochemical procedures that allow obtaining the tracer in purity high enough for final formulation and injection starting from a suitable precursor and the radionuclide freshly produced by a cyclotron. The general approach requires the use of big and complex devices that need to be screened for radioactivity and handled by qualified personnel. The wide spreading of PET all over the world is therefore stressing the need for an overall simplification of the radiosynthetic steps and any innovation in this direction will lead to a better service to final users of these techniques, the human beings.
PET radiopharmaceuticals are compounds strictly related to molecules of life such as sugars, nucleosides, amminoacids or receptor ligands. These structures must comprise also a positron-emitting nuclide that is inserted in the last steps of the chemical synthesis (during the labelling step), shortly before the patient injection. The atoms amenable for insertion and with suitable radioactive features are commonly 11C, 13N, 15O and 18F. Among all of these atoms, 18F is the most employed because of its relatively “long” half-life (120 minutes) that allows more complex reaction schemes and the possibility of “satellite centers” for the production and selling of the final radiolabelled product. Therefore, the efforts will be focused towards the production of devices able to handle this nuclide, bearing in mind that the technology developed could be a base for similar equipment to be used with other nuclides such as 11C (shorter half-life), 94Tc, 64Cu, 76Br (longer half-life) just to name few.
The main radiosynthetic steps are summarized in the following scheme. [18F]F- is produced by the cyclotron from enriched 18H2O proton bombardment and inserted into the pharmaceuticals generally by nucleophilic substitution reactions under proper activation conditions. Precursors amenable of easy nucleophilic displacement (hence bearing good leaving groups such as halogens, nitro, tosylates, etc.) are essential for a good outcome of the labelling reaction; this implies that it is sometimes necessary to use a “pre-precursor” that, once labelled with high radiochemical yield, has to be further (and quickly) chemically modified to obtain the final desired product.
On the basis of this schematic, the main operations during radiosynthesis and their implementation into the device are:
- one or more steps of mixing for addition of reagents, solvents,…
- concentration of the aqueous [18F]F- species via anion exchange columns or electrophoretic techniques that allow for direct interfacing to the cyclotron
- one or more steps of heating (for concentration, dehydration,..)
- one or more extraction steps for intermediate purification
- final product purification, via HPLC or continuous flow microfluidic separation
During the ROC project, all these steps will be developed inside some modules of a microfluidic architecture which can be used for standard synthesis protocols as well as for R&D of new radiopharmaceuticals. Emerging technologies in the field of micro reactors and micro total analysis systems (μ–TAS) will be applied to the synthetic pathways typical for radiopharmaceuticals, in order to improve the traditional approach in terms of efficiency and safety.
