State of the art of radiochemistry for11C and18F PET tracers

Positron emission tomography (PET) predominantly relies on the use of carbon-11 and fluorine-18 radiolabeled pharmaceuticals. The growing interest in the fluorine-18 radionuclide for PET undoubtedly results from its convenient half-life (t1/2=109.8min) and clean decay profile. The special interest of carbon-11 (t1/2 = 20.38min) is due to its prevalence in almost all drug molecules, allowing isotopologue labeling of the bioactive molecule as well as the possibility to radiolabel at different positions. Radiochemistry includes the production of these short-lived radionuclides in a cyclotron and the development of rapid synthetic methods for the introduction of these nuclides into a drug molecule, as well as the development of fast purification, analysis and formulation techniques. Radiochemistry is the driving force in molecular PET imaging and the field is still changing significantly. Radiochemistry of carbon-11 and fluorine-18 is dominated by nucleophilic substitution of a heteroatom with a methylating agent (11CH3I, 11CH3OTf) or a good leaving group with a fluoride source (i.e., tosylate, triflate, halogen with [18F]KF/K222 or [18F]TBAF). In recent years however, radiochemistry has developed immensely with novel reactions and approaches. From cross-coupling reactions, [11C]CO2 fixation reactions, organolithium reagents, chemical and electrochemical [11C]CO2 decomposition, 11C-carbonylation reactions, the usage of boronic acid ester and iodonium precursors, 18F-deoxyfluorination of phenols via Ru π-complexes, fluorodestannylation and preparation of 18F-building blocks. This article aims at illustrating the state-of-the-art radiolabeling reactions currently available for incorporating the positron emitter radionuclides carbon-11 and fluorine-18 in drug molecules.