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Fluorine-18-chemistry: [18F]FDG and beyond
mit Frédéric Dollé

Molecular in vivo imaging with the high-resolution and sensitive Positron Emission Tomography (PET) technique requires the preparation of a positron-emitting radiolabelled probe or radiotracer. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice due to its adequate physical and nuclear characteristics but also due to the successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), the currently most widely used PET-radiopharmaceutical and manifestly a motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry.

Besides a few exceptions, radiofluorinations involving fluorine-18 of high specific radioactivity (> 200 GBq/µmole) had been, until recently, limited to nucleophilic substitutions in homoaromatic and aliphatic series with [18F]fluoride. Recent advances in fluorine-18 chemistry include the use of moderate specific activity fluorine ([18F]F2, 3.7-25 GBq/µmole) for aromatic electrophilic substitutions, as well as the use of iodonium salts as precursors for labelling, allowing fluorination of electron-rich arenes using homoaromatic nucleophilic substitutions and [18F]fluoride. Recently, the discovery of the naturally-occurring enzyme fluorinase, catalysing fluorination with fluoride via a nucleophilic mechanism, opens new strategies for carbon-[18F]fluorine bond formation. Finally, considering chemical structures showing a fluoropyridine moiety, nucleophilic heteroaromatic substitution at the ortho-position with no-carrier-added [18F]fluoride appears today as a highly efficient method for the radiosynthesis of radiotracers and radiopharmaceuticals of high specific radioactivity.

This presentation aims at giving an overview of fluorine-18 chemistry and will be illustrated with some representative examples taken from the laboratory.


Fluorine-18-labelling of macromolecules for PET imaging
mit Bertrand Kuhnast

High-molecular-weight bioactive chemical structures (commonly termed macromolecules), such as oligonucleotides, peptide nucleic acids, peptides, proteins, antibodies, diabodies and others are increasingly proposed as radiopharmaceuticals. Their applications are gaining importance in nuclear medicine for therapy on one side, but also for diagnostic purposes with in particular the development of “macroprobes” labelled with positron-emitters for PET. Fluorine-18 can be considered as an isotope of choice for the labelling of macromolecules, among the other conventional short-lived positron-emitters. It can be reliably and routinely cyclotron-produced at the multi-Curie level as [18F]fluoride ions and efficiently incorporated into various chemical structures. Its half-life (109.8 minutes) allows multi-step synthetic approaches and is long enough to give access to relatively extended imaging protocols, often required with macromolecules. Methods for radiolabelling macromolecules with fluorine-18 have been of interest for several decades. Today, the generally accepted approach involves a prosthetic group in the form of a small fluorine-18-labelled reagent that is coupled chemoselectively to an appropriate reactive function of the macromolecule. This foreign-labelling strategy has the advantage of offering a flexibility in the choice of chemical routes, including those requiring drastic chemical conditions for the preparation of the labelled prosthetic reagent, while the conjugation of the latter with a macromolecule can then be done using milder conditions needed to preserve the latter's integrity.

This presentation aims at giving an overview of the well-established and emerging strategies for the prosthetic labelling of macromolecules and will be illustrated with some representative examples, drawn, when it is relevant, from our own experience at SHFJ.