Transfer of fluorinase mediated C-18F bond formation technology to the clinical environment for tumor imaging by PET

Several years ago the St Andrews laboratory isolated a very unusual enzyme in that it had the ability to form carbon-fluorine bonds from inorganic fluoride ion. This enzyme was isolated and the gene identified and over-expressed in E.coli. The enzyme has emerged as an extremely useful catalyst for incorporating the isotope F-18 into an organic molecule. Using other enzymes in combination with the fluorinase enzyme the St Andrews laboratory have been able to make several novel fluorine-18 labelled products in time scales (1-2 hours) suitable for exploring the products as imaging agents, by positron emission tomography. We have begun to collaborate with the Aberdeen lab and have some preliminary data which shows that one of these molecules is actively transported into breast cancer cells, and also that one of these compounds can suitably image a rat. This Discipline Hopping grant will give us the opportunity to combine the expertise of the labs and establish if the fluorinase mediated catalysis of 18F-C bonds can be transferred into a clinical hot laboratory environment, and to establish if some of the molecules that can be prepared enzymatically have potential as imaging agents for cancer (oncology) and/ imaging the brain (neurology).

Positron emission tomography (PET) is growing rapidly through the Western world and developing countries as a diagnostic imaging tool for cancers and degenerative neurological disorders. In general the link between fluorine chemistry and pharmaceutical/medical applications is growing and all indications are that this will continue. The fluorinase enzyme was discovered in 2002 in St Andrews (Nature 2002, 416, 279) and it has been over-expressed and its structure (X-ray) and mechanism elicidated (Nature, 2004, 427, 561). The enzyme catalyses a reaction of fluoride ion and SAM to generate 5 -FDA and L-methionine. It has attracted attention as an enzymatic method of generating C-F bonds from inorganic fluoride. The fluorinase offers an entirely new method for the catalysis of C-F bonds. 18F is an important isotope for PET. We have shown now that it works well as a catalyst for the synthesis of 18F-C bonds. The objective of this programme is to demonstrate now that the fluorinase technology can be practically transferred to the clinical environment for clinical imaging in a collaboration between St Andrews University Centre for Biomolecular Sciences, and the John Mallard PET Centre - Aberdeen University at Aberdeen Royal Infirmary.