Periodic Reporting for period 1 - HYPOXFLU ([18F]Fluorination of alkylCF3 and alkylCF2CF3 chains-Application to hypoxia biomarkers for PET imaging.) Reporting period: 2015-03-16 to 2017-03-15 Summary of the context and overall objectives of the project Hypoxia is the pathological condition of insufficient oxygen supply, characteristic of advanced solid tumors, usually resulting in a resistance to radiation- and chemotherapy and consequently a negative prognostic factor for patients. A number of methods to measure hypoxia exist, however, as tumors are highly heterogeneous, 3D imaging methods as PET imaging for example, are still crucial. 18F-based Positron Emission Tomography (PET) imaging is a non-invasive and sensitive in-vivo imaging modality that can provide quantitative measurements of biological processes, allowing clinicians to make an accurate diagnosis and prognosis and so to provide an effective personalized treatment region, increasing a patient’s quality of life. However, progress in this field is currently hindered by the lack of methods that allow the rapid and efficient late-stage introduction of 18F into targets of interest. Among the known biomarkers for the detection of hypoxia, [18F]FMISO has been studied extensively, both preclinically and clinically, in different cancer types. Despite being the most widely used PET agent for regional hypoxia mapping, concerns have been raised about the use of [18F]FMISO. EF5 and EF3 are second-generation biomarkers, and their potential advantages over other hypoxia biomarkers is well documented. However, the use of their 18F counterparts for PET imaging is sparse, due to a fundamental lack of suitable radiochemical transformations. Therefore, the development of novel, efficient methods to reach these motives would not only facilitate widespread research into [18F]EF5 and [18F]EF3, but also the use of alkyl [18F]CF3 or [18F]CF2CF3 motifs more generally in the design of radiotracers, as a number of therapeutic agents and/or biomarkers containing perfluorinated chains are described in the literature. The overall objectives of this project are 1) to develop a novel methodology for the labelling of alkyl-CF3 and alkyl-CF2CF3 chains, 2) to develop an automated radiolabelled synthesis of tumor hypoxia biomarkers [18F]EF3 and [18F]EF5 as a proof of concept, and 3) to perform an in-vivo pre-clinical comparative study of the properties of [18F]FMISO, [18F]EF3 and [18F]EF5 for imaging hypoxia in small animals. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In order to develop a novel methodology for the labelling of alkyl-CF3 and alkyl-CF2-CF3 chains, our first objective was to synthesize model difluoroboronic species as starting material. These compounds are required, in our strategy, to apply the copper mediated [18F]fluorination of (hetero) arene boronic esters recently described in our laboratory. However, despite our efforts, these compounds appeared to be very difficult to synthesize, probably due to their potential unstability. Nevertheless, we were able to obtain various (2-aryl-1,1,2,2-tetrafluoroethyl)trimethylsilanes, presenting a great interest in the field of perfluorinated chemistry, as Ruppert-Prakash analogues. After some investigations, the copper-mediated cross-coupling of these reagents with various (hetero)aryl halides in mild conditions was performed. This new methodology allows the rapid access to a class of highly valuable 1,1,2,2-tetrafluoro-1,2-arylethane derivatives presenting with a CF2CF2 unit flanked by two aryl (or heteroaryl) groups, used in liquid-crystalline materials or in medicinal chemistry. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Fluorine chemistry has made and continue to impact tremendously medicinal chemistry and molecular imaging (PET). Fundamental research in fluorine chemistry is always needed to develop new synthetic routes to address the fluorination of specific molecules of interest. Our new methodology represents a progress in the field of fluorine chemistry. Indeed, this reaction is an improvement over current fluoroalkylation reactions due to the mildness of the reaction conditions. Moreover, this new methodology allows the rapid access to a class of highly valuable 1,1,2,2-tetrafluoro-1,2-arylethane derivatives. As observed in the literature, this motive is used in liquid-crystalline materials or in medicinal chemistry. We anticipate that this new process will facilitate research programs focusing on the discovery of new drugs and high performance materials. scheme.gif
