FLUOPET

Late Stage Fluorination for Positron Emission Tomography Applications

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 Obiettivo del progetto (Objective)

'Positron Emission Tomography (PET) is a powerful non-invasive, real-time imaging technology that can be used to identify and characterize human disease, but is currently limited by deficiencies in chemistry. While simple molecules can be efficiently prepared, more complex, biomedically interesting molecules often cannot. The short half-life of [18F] (110 min) dictates severe restrictions on the chemical synthesis of PET tracers. Fluoride introduction must occur at a late stage of the synthesis, ideally as the last step, to avoid unproductive decay of the [18F] nucleus before injection into the body. Due to the limited functional group compatibility with conventional fluorination reactions employed today and the short half-life, the synthesis of PET tracers is limited to a small number of simple molecules. The high specific-activity isotopes – thus low mass – dictate a need for unusually high chemical reaction rates and efficiencies, which are met by only a handful of methods. The Ritter group at Harvard has developed a unique technology based on the concept of late-stage fluorination as a tool to streamline the synthesis of complex fluorinated molecules using [19F]. Late-stage fluorination has the potential of significantly increasing the number of [18F]-PET agents and their radiochemical yield. During this Fellowship we wish to develop and validate a general and robust late-stage fluorination chemistry with [18F] for the synthesis of PET tracers, using the “know how” of the Ritter group in the field of modern C-F bond formation. The new technology developed will be initially applied to the preparation of [18F]-fluorodeoxyestrone as a first “proof of concept”. In a more advanced stage, the project will deal with the translation of the new technology from Harvard to the ETH Centre for Radiopharmaceutical Science (Ametamey group), where will be used for the preparation of new [18F]-PET tracers for imaging PET the Metabotropic Glutamate Receptor Subtype 5 (mGluR5)'

Introduzione (Teaser)

Positron emission tomography (PET) exploits metabolism of small amounts of a radioactive tracer molecule to evaluate disease or damage. Novel chemicals promise to expand the capabilities of PET from simple glucose to complex molecules like proteins.

Descrizione progetto (Article)

The PET tracer is prepared by tagging a molecule normally used by the body with a radioactive atom. PET often employs glucose, the body's fuel. Glucose metabolism (building up and breaking down) in terms of rate and location provides important information about biochemical changes associated with the onset or progression of a disease.

Glucose is most often tagged with radioactive fluorine to create a radionuclide called fluorodeoxyglucose (FDG). FDG is injected intravenously. As it decays, it emits positrons and eventually creates gamma rays that can be detected by a scanner.

Currently, PET is limited by the short half-life of fluorine-18 (18F) and its small number of compatible functional groups. This means it must be introduced close to injection time and can only tag a small number of simple molecules. Scientists sought to expand the capabilities of PET with EU funding of the project 'Late stage fluorination for positron emission tomography applications' (FLUOPET).

Building on recent advances by partner scientists in late-stage fluorination with 19F, investigators sought first to improve those methods. They demonstrated excellent success using a common commercial reagent (PhenofluorTM) at room temperature, meaning compatibility with temperature-sensitive substrates. In addition, the synthesis process substantially reduced or even eliminated typical side reactions and demonstrated broad functional group compatibility with synthetically useful selectivity.

In the second year, the team focused on adaptation of the methods from 19F to 18F. Numerous PhenofluorTM-type reagents were successfully prepared. However, their selective fluorination with 18F has proved more complicated. Experiments are ongoing to improve it.

During the development of analogues of PhenofluorTM, scientists serendipitously created a solid complex containing an important reagent for trifluoromethylation (trifluoroiodomethane, or CF3I). It is typically in gaseous form in which its usefulness was more limited. Researchers demonstrated its practicality and sometimes greater reactivity compared to the gaseous form. A patent application has been filed and a publication submitted.

FLUOPET launched the development of improved PET tracers for imaging the metabolism of complex molecules such as neurotransmitter receptors. Continued work is expected to greatly advance the capabilities of an already powerful non-invasive technique to diagnose and follow the progression of numerous diseases.