Difluorocarbene: Synthesis, Reactivity and Applications for PET Imaging
Lead Research Organisation:
University of Oxford
Department Name: Oxford Chemistry
Abstract
Positron Emission Tomography (PET) is a non-invasive quantitative imaging technology that can detect pre-symptomatic biochemical changes in body tissues where no evidence of abnormality from computed tomography (CT) or Magnetic Resonance Imaging (MRI) are detectable or before structural changes occur from disease. This technology helps researchers understanding diseases and can assist clinicians in the selection of the best treatment for an individual patient, provided that competent biomarkers are available. The unrivalled sensitivity of PET makes this technique also suitable to address questions fundamental to drug development for oncology, cardiology, neurosciences and inflammatory diseases. One of the most commonly used positron-emitting radioisotopes is 18F, in part due to the extensive use of [18F]fluorodeoxyglucose in the clinic and the importance of fluorine substitution in the context of drug discovery. The short half-life of 18F (110 min) dictates a preference for protocols based on late stage fluorination. The enabling technology that underlies all forms of [18F]radiotracer imaging is [18F]radiotracer chemistry, because it is required for the development of [18F]radiotracer probe molecules. Radiotracer chemistry is a unique discipline that demands special reactions, equipment, techniques, understanding, and training. Its uniqueness stems from the unique behavior of chemical reactions conducted at the tracer-level scale to obtain products of sufficiently high specific activity, the need for efficiency and speed associated with performing chemical transformations and product purifications on materials that are labeled with short half-life radionuclides such as [18F]. The aim of this project is to develop new [18F]radiochemistry with the view to access much needed [18F]radiotracers currently difficult or not possible to prepare. We propose several methods to [18F]label molecules containing CF3 and CF2 motifs commonly found in pharmaceutical drug candidates and biomarkers. The project based on solid published preliminary data exploits the reactivity of difluorocarbene and easily accessible [18F]fluoride used in combination with readily available precursors and co-reagents. The emphasis is on the development of [18F]radiotracer chemistry methods that are versatile and easy to translate from molecule to molecule to advance the field of PET imaging in the UK and abroad.
Planned Impact
The proposed project will examine the value of difluorocarbene as a reactive entity to access [18F]radiotracers featuring either a CF3 or CF2 sub-motif. The beneficiaries of this research are scientists interested in using PET technology to understand disease states and complex biological processes as well as the academic community interested in fluorine chemistry and [18F]radiochemistry. The other group of beneficiaries are preclinicians and clinicians who may consider PET imaging as a tool to diagnose disease states at an early stage of development. The pharmaceutical industrial sector will also benefit from this research as PET is an enabling technology allowing the acquisition of in vivo data on drug candidates earlier in the drug development pipeline. This is particularly critical for CNS diseases.
The impact of this research on the global economic performance and the economic competitiveness of the United Kingdom is important. The science proposed will enhance the use of PET imaging and in the process improve will healthcare, the health and quality of life of patients. This is because PET produces a three-dimensional image of functional processes in the body. Common applications include: early diagnosis of cancer, heart disease, epilepsy, Alzheimer Parkinson disease; locating accurately and staging malignant disease; monitoring in a non invasive manner the effects of treatment; reducing or eliminating ineffective and unnecessary treatment; and also streamlining drug discovery to decrease attrition rate.
The impact of this research on the global economic performance and the economic competitiveness of the United Kingdom is important. The science proposed will enhance the use of PET imaging and in the process improve will healthcare, the health and quality of life of patients. This is because PET produces a three-dimensional image of functional processes in the body. Common applications include: early diagnosis of cancer, heart disease, epilepsy, Alzheimer Parkinson disease; locating accurately and staging malignant disease; monitoring in a non invasive manner the effects of treatment; reducing or eliminating ineffective and unnecessary treatment; and also streamlining drug discovery to decrease attrition rate.
People |
ORCID iD |
Veronique Gouverneur (Principal Investigator) |
Publications
Tredwell M
(2014)
A general copper-mediated nucleophilic 18F fluorination of arenes.
in Angewandte Chemie (International ed. in English)
Khotavivattana T
(2015)
(18)F-Labeling of Aryl-SCF3, -OCF3 and -OCHF2 with [(18)F]Fluoride.
in Angewandte Chemie (International ed. in English)
Gouverneur V
(2015)
Silver-Mediated 18F-Labeling of Aryl-CF3 and Aryl-CHF2 with 18F-Fluoride
in Synlett
Preshlock S
(2016)
18 F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography
in Chemical Reviews
Campbell MG
(2016)
Bridging the gaps in 18F PET tracer development.
in Nature chemistry
Preshlock S
(2016)
Enhanced copper-mediated (18)F-fluorination of aryl boronic esters provides eight radiotracers for PET applications.
in Chemical communications (Cambridge, England)
Wilson TC
(2016)
Radiosynthesis of SPECT tracers via a copper mediated 123I iodination of (hetero)aryl boron reagents.
in Chemical communications (Cambridge, England)
Taylor NJ
(2017)
Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands.
in Journal of the American Chemical Society
Verhoog S
(2018)
18F-Trifluoromethylation of Unmodified Peptides with 5-18F-(Trifluoromethyl)dibenzothiophenium Trifluoromethanesulfonate.
in Journal of the American Chemical Society
Sap J
(2019)
Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride
in Chemical Science
Description | Novel methods for the labeling of drug candidates and radioligands for application in drug discovery, as well as radiotracers and radioligands synthesis. More precisely: Novel methods for the labeling of aryl-CF3 and arylCHF2 First method for the labeling of aryl-OCF3, OCHF2 and SCF3 The key finding have been published in a manuscript entitled: Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride. In this manuscript we have reported the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate- which is a difluorocarbene precursor, and cyclotron-produced non-carrier added [18F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated 18F-fluorodecarboxylation. |
Exploitation Route | The methods developed with the grant have been used in drug discovery, as well as radiotracers and radioligands synthesis. It has attracted the interest of pharmaceutical companies in the UK and oversea. It has allowed us to secure a new collaboration with Pfizer (USA) (Studentship) |
Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | http://gouverneur.chem.ox.ac.uk/home |
Description | This EPSRC-funded project is aimed at developing new methods for the labelling of important structural motifs to facilitate go or no go decision in the context of drug discovery. The overall aim is to decrease the attrition rate that the pharmaceutical industry is currently facing in the UK and worldwide. The postdoctoral research scientist appointed on this EPSRC-funded project did contribute significantly towards this overall aim prior and during his appointment as an EPSRC-funded PDRA. Prior to his appointment, his work in the Gouverneur's research group led to an important publication that disclosed a new method to label arenes (Angew. Chem. Int. Ed. 2014, Patent entitled "Fluorination method" under the following publication number: WO 2015/140572 (in PCT phase). This work was continued during his appointment as an EPSRC-funded PDRA (this grant), and will lead to at least two additional publications in high profile journals. In addition, significant advances were made on the labelling of difluorocarbenes, and this work has the potential to make a significant impact in the pharmaceutical industry. This study has allowed for the development of the first method leading to the labeling of OCF3, SCF3 and OCHF2 ,as well as an alternative method for the labeling of aryl-CF3 and aryl-CHF2. These were the motifs that were targeted in the grant proposal. So in that sense, we have fullfilled the objectives of the grant although the proposed method had to be slightly modified for successful completion. |
First Year Of Impact | 2014 |
Sector | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal,Economic |
Description | 18F-Difluoromethylation: The Missing Link in Radiochemistry for Positron Emission Tomography |
Amount | £506,885 (GBP) |
Funding ID | EP/V013041/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2021 |
End | 12/2024 |
Description | H2020-MSCA-ITN-2016-FLUDD |
Amount | € 1,341,024 (EUR) |
Funding ID | EU project 721902 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2017 |
End | 02/2021 |
Description | This project has led to further collaboration with industry (IMANOVA, Pfizer, ABX and UCB) |
Organisation | Pfizer Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Extension to the CF3 methodology to the radiolabeling of drug motifs of interest to the pharmaceutical sector- Funding towards delineating the scope and limitation of the method Funding towards the development of novel superior methods towards the labeling of OCF3 and OCHF2 |
Collaborator Contribution | 50% studentship (contribution to stipend and fees) |
Impact | The student has started in October 2016 |
Start Year | 2016 |
Description | General Public Talk Merton College |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | General public talk explaining why radiochemistry is important and how it impacts healthcare and ultimately patients. |
Year(s) Of Engagement Activity | 2016 |
Description | International Visiting Research Scholar public talk, Peter Wall Institute for Advanced Studies, University of British Columbia, Vancouver, Canada |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The position of Fluorine in the periodic table confers to this element unique properties that have been explored by chemists in many creative ways. Fluorine-containing molecules have found applications in material sciences, the pharmaceutical and agrochemical industries, and in medical sciences. In this lecture, Véronique Gouverneur will illustrate how the most recent advances in fluorine chemistry and radiochemistry can have a profound impact on medical imaging for immediate applications in diagnostic and pharmaceutical drug development. |
Year(s) Of Engagement Activity | 2017 |
URL | https://pwias.ubc.ca/event/fabulous-fluorine |
Description | The Dorothy Hodgkin Memorial Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 'Fabulous Fluorine' The position of Fluorine in the periodic table confers to this element unique properties that have been explored in many creative ways. This lecture discussed how fluorine chemistry has advanced medical imaging for diagnostic and pharmaceutical drug development. This lecture is part of the Oxford International Women's Festival. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.rsc.org/events/detail/30603/dorothy-hodgkin-memorial-lecture |