Fluorine-18 Radiopharmaceuticals Research Articles

Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging.

Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-18F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-18F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed. A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion. CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

Chemistry Considerations for the Clinical Translation of Oncology PET Radiopharmaceuticals.

Positron emission tomography (PET) has proven to be an invaluable tool in the staging and management of disease in oncology; however, [18F]fluorodeoxyglucose ([18F]FDG) remains the most widely used PET radiopharmaceutical despite the large financial investment in novel radiotracer development. We report our perspective and experience of translating radiopharmaceuticals into clinical studies, discussing the PET development pipeline from a chemistry perspective. We hope that, by identifying potential points of attrition along the pipeline and suggesting solutions to these problems, we may help others take their preclinical radiotracers into human studies. This review focuses primarily on the development of fluorine-18 radiopharmaceuticals, although the broader field of radiometal chemistry is considered where the translation journey is similar.

Single center experience on the production of fluorine-18 radiopharmaceuticals using a 7.5\xa0MeV cyclotron: capabilities and challenges

A plethora of cyclotron options have been developed to fulfil the demands of nuclear medicine industries in PET and SPECT radioisotopes. As a remote site, the difficulties of transporting fluorine 18 radiopharmaceuticals for PET examinations were overcome by the installation of a 7.5 MeV cyclotron for in-house production. The addition of a third-party synthesis module enabled the synthesis of 7 additional radiotracers according to a ‘’dose on demand’’ principle. Radiochemical yield is considered the primary factor in producing sufficient activity for a single patient dose, since low energy cyclotrons can only offer low initial activities. We hereby report the average radiochemical yields, synthesis times and doses per production for [18F]FDG, [18F]PSMA-1007, [18F]DOPA, [18F]FET, [18F]FLT, [18F]FMISO, [18F]Choline and [18F]FES using a BG75 cyclotron and a Neptis Mosaic-RS. Additionally, the presence of radionuclidic impurities in the final product was examined.

18 F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent.

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [18 F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [18 F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [18 F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [18 F]fluoride source.

Fluorine-18 radiopharmaceuticals beyond [18F]FDG for use in oncology and neurosciences

Positron emission tomography (PET) is a rapidly expanding clinical modality worldwide thanks to the availability of compact medical cyclotrons and automated chemistry for the production of radiopharmaceuticals. There is an armamentarium of fluorine-18 ((18)F) tracers that can be used for PET studies in the fields of oncology and neurosciences. However, most of the (18)F-tracers other than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) are in less than optimum human use and there is considerable scope to bring potentially useful (18)F-tracers to clinical investigation stage. The International Atomic Energy Agency (IAEA) convened a consultants' group meeting to review the current status of (18)F-based radiotracers and to suggest means for accelerating their use for diagnostic applications. The consultants reviewed the developments including the synthetic approaches for the preparation of (18)F-tracers for oncology and neurosciences. A selection of three groups of (18)F-tracers that are useful either in oncology or in neurosciences was done based on well-defined criteria such as application, lack of toxicity, availability of precursors and ease of synthesis. Based on the recommendations of the consultants' group meeting, IAEA started a coordinated research project on "Development of (18)F radiopharmaceuticals (beyond [(18)F]FDG) for use in oncology and neurosciences" in which 14 countries are participating in a 3-year collaborative program. The outcomes of the coordinated research project are expected to catalyze the wider application of several more (18)F-radiopharmaceuticals beyond FDG for diagnostic applications in oncology and neurosciences.

Arylation of anilines: formation of diarylamines using diaryliodonium salts

Extensive studies on the reaction of the fluoride ion with diaryliodonium salts demonstrated that this is a generic process for the formation of fluoroarenes and has particular advantages for the preparation of fluorine-18 radiopharmaceuticals. During these studies it became apparent that nucleophiles other than the fluoride ion may be employed for generating substituted aromatics. This approach can be applied, using substituted anilines as the nucleophilic reagent, to the formation of a range of diarylamines in good yield. Optimised conditions for the reaction of a diaryliodonium salt with an aniline utilise TFA as the preferred counter-ion in DMF (130 °C, 24 h).

Determination of residual Kryptofix 2.2.2 levels in [ 18F]-labeled radiopharmaceuticals for human use

4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix ® 2.2.2) is used in the routine preparation of [ 18F]-labeled tracers employed in positron emission tomography (PET) imaging. Confirming the absence of Kryptofix ® in radiopharmaceuticals is a quality control criterion required before they can be released for human use. Analysis of Kryptofix ® levels using the iodoplatinate spot-test can be complicated by false-positive results due to nitrogen containing tracers and/or false-negative results caused by added stabilizers. To overcome this issue, we have developed a universal TLC method for the rapid and reliable determination of Kryptofix ® levels in the wide range of fluorine-18 radiopharmaceuticals we prepare, including complex multi-component formulations.

Chemistry of fluorine-18 radiopharmaceuticals

Chemistry of fluorine-18 radiopharmaceuticals