Radiofluorination is the process by which a radioactive isotope of fluorine is attached to a molecule and is preferably performed by nucleophilic substitution using nitro or halogens as leaving groups. Fluorine-18 is the most common isotope used for this procedure. This is due to its 97% positron emission and relatively long 109.8 min half-life. The half-life allows for a long enough time to be incorporated into the molecule and be used without causing exceedingly harmful effects. This process has many applications especially with the use of positron emission tomography (PET) as the aforementioned low positron energy is able to yield a high resolution in PET imaging.
History
The first notable radiofluorination synthesis was performed in 1976 for the synthesis of Fluorine-18 labeled fludeoxyglucose. In the 1980s this molecule was discovered to accumulate in tumors of cancer patients. Since this time, this molecule has become a standard in PET imaging of cancer, and currently the only FDA-approved substance to do so. In recent years, research is being performed to find alternatives to the fludeoxyglucose molecule. These new molecules are bifunctional labeling agents that can attach to proteins or peptides to label not only cancer, but also amyloid plaques and inflammatory processes.
Procedure
Due to the ongoing research involving radiofluorinated molecules and their various uses, the demand for suitable syntheses has increased over the years. In order for synthetic methods to be considered viable, the process must be rapid and efficient as well as compatible with the forms of 18F with are available. In many cases, the synthesis must also be capable of regio- and stereo-specificity.
Typically, radiofluorinated products are synthesized using nucleophilic or electrophilic substitution processes. One classical method for radiofluorination is the Balz-Schiemann reaction, or a modified Balz-Schiemann reaction with [18F] F−. Electrophilic substitution reactions typically make use of [18F] F2 as a precursor which can then be added to an array of molecules such as alkenes, aromatic rings, and carbanions [21]. However, methods utilizing [18F] F2 are at a disadvantage due to the loss 50% of the input activity in the form of [18F] F−. To facilitate these procedures the reaction may also be carried out within a microfluidic chamber.
Uses
One of the most popular uses of radiofluorination is its application in PET scans. Positron emission tomography (PET) is a widely used imaging technique in the field of nuclear medicine. With applications in research and in diagnosis, a PET scan can be used to image tumors, diagnose brain disease, and monitor brain or heart function [8,9,12]. These images are created with the aid of radiotracers that emit positrons which decay via an annihilation reaction to generate two 510 KeV photons that are then detected and used to reconstruct images using the same software utilized in X-Ray CT units. The gamma rays are then emitted nearly 180 degrees from each other and their detection allows the ability to pinpoint the source, thus creating an image. One of the most popular isotopes used as a positron emitting radiotracer is fluorine-18. This isotope is particularly advantageous due to its short half-life of approximately 109.8 min, its decay being 97% positron emission, its ease of production, and its energy being low (0.64 MeV). Therefore, the radiofluorination procedure is incorporates the radioactive isotope of choice in order to create the images.
Another application in the field of radiofluorination chemistry lies in the field of biofuels. Recent interest has been given to the exploration of lignocellulostic material as a biofuel source. Given that it is the most plentiful renewable carbon source in the biosphere, it is a natural choice for this purpose. The composition consists of three elements—hemicellulose, cellulose, and lignin. It is the last of these three, lignin, that presents the greatest obstacle to the efficient use of such material as a feasible biofuel source. The recalcitrant chemical nature of the lignin molecule currently requires an extensive and expensive process to degrade for bioethanol. Current research is being conducted to find more economical ways to breakdown this lignin barrier. This research will explore the use of radiofluorination with the fluorine-18 isotope to search for places in nature that lignin is being degraded. The radioactive fluorine will be attached to lignin-degradation products in order to search for enzymes in nature that breakdown lignin. This will help to make the process more efficient for use in biofuel production.