De Novo Carbon-11 Chemistry: New and Explorative Radiolabelling Strategies for PET

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

Medical imaging technology is currently revolutionising our understanding of the human body, the human mind and the diseases that affect us. Imaging techniques are now routinely used for the diagnosis of illnesses and to assist in the discovery of new treatments and cures. Many of us are now familiar with the power of modern scanning technology, such as ultra-sound, MRI or CT, available within our hospitals for the diagnosing conditions ranging from broken bones to stroke. Positron Emission Tomography, or PET imaging for short, is certainly less familiar to the general public. Recent technological advances in computers, material sciences and radiochemistry have now enabled the routine use of PET imaging in many of the UK's major hospitals. PET is characteristically different from the other imaging techniques as it is primarily used to give a so-called 'functional' picture, as opposed to a purely anatomical image, of biological processes. The type of functional information gained from PET is extremely useful for better understanding biological processes involved in diseases such as cancer and neurodegenerative illnesses such as Alzheimer's. PET imaging requires the injection of a radioactive tracer into the body prior to scanning. The synthesis of these tracer molecules is particularly challenging because they need radioactive isotopes that have very short half-lives. PET tracers are typically prepared in the hours or even minutes prior to a scan. Chemistry therefore plays a hugely important role in the PET imaging process, both for the synthesis of existing tracers and the development of new ones. Currently, however, there is a limited range of chemical reactions that can be used to prepare tracers for PET. To develop new tracer molecules, which will ultimately lead to a greater understanding of disease processes and help to find treatments, new types of chemistry and technology need to be conceived. The aim of this research proposal is to develop completely new radiochemistry for the synthesis of new radiolabelled molecules that are currently inaccessible, and to use these new tracer molecules to probe the hall-marks of cancer. The new radiochemistry to be developed will be based on using a small reactive molecule, called carbon disulfide, that will be labelled with a radioactive carbon-11 atom. This so-called 'C-11 carbon disufide' will then be reacted to produce labelled molecules that will find applications in PET imaging.

Planned Impact

PET imaging sits at the boundary between the physical sciences and medicine. It is leading to new discoveries in biology and medicine by exploiting radiolabelling tracers that specifically target molecular receptors and damaged tissues in vivo. This project, by developing fundamental chemistry and radiochemistry, will impact both within the physical sciences and find future applications in medicine, as such, there will be a number of beneficiaries of this research. For example, in terms of immediate beneficiaries, those working in the PET radioisotope production and PET radiolabelling fields will be to able to directly apply the labelling techniques and production methods resulting from this project. PET radiochemists will be able to exploit newly reported precursror molecules and labelling routes for the development of labelled molecules and tracers. In the longer term, others working directly in the field of PET imaging (biologists and clinicians), initially within the cancer imaging, will be able to apply the proposed CXCR4 imaging agents either as a diagnostic marker for cancer and metastasis, or for the development of therapeutics targeting this receptor. Indirectly, this research - both explorative radiolabelling aspect and the applied tracer production of [C-11]IT1t - will find much wider application. Such novel labelling methods have the potential to be applied to a range of tracer molecules that could find applications in other areas of PET imaging and medicine, for example in neurology, cardiology and pysciatry. Other potential beneficiaries include the pharmaceutical sector who may also be able to apply this research within drug discovery programmes. For example, this work will enable isotopic radiolabelling of molecules in atomic positions that were previously inaccessible with exiting technology and thus could be used to give information on the accumalation, distribution and metabolism of lead compounds under drug development. Additionally, the new tracers proposed under this project will be expected to have higher affinities and specificities for the CXCR4 receptor and may therefore lead to the development of better assays for assessing therapeutics. It is the expectation that in the longer term there will a clinical benefit arising from improvements in cancer imaging or therapeutic developments as a result of this research and will therefore impact on health and well being. In the UK, PET imaging is finding increasing applications for clinical diagnosis and as tool for research purposes. The new chemisties developed under this project will aid the future expected growth of PET and ensure the UK has a competitive edge in the discovery of new labelling technology, biomarkers and imaging agents. Thus it will directly contribute both to our society in terms of potential health benefits and to the economy as the resulting discoveries find commerical applications in the healthcare field. Such direct benefits to healthcare will happen only in the much longer term and may not be realised for 10-20 years after the project.
The staff and students that work on this project will gain a broad range of research skills and training in radiolabelling techniques, radio-analytical methods, tracer production, PET biology and imaging sciences. They will experience all aspects of the PET imaging process from intial radioistope production to the application of tracers for imaging. Working in both an academic environment at IC and in close collaboration with our inductrial partner, Imanova, will give staff the necessary research skills and understanding of the professional expectations within industry to seek employment in high level academic or industrial research sectors.
 
Title Animated PET imaging video 
Description A short animated video clip describing how PET imaging works 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact The video, released only in January 2016, has received several thousand YouTube views. 
URL https://www.youtube.com/watch?v=yrTy03O0gWw
 
Description This research has provide a new route to prepare radiolabelled compounds that facilitate the production of PET radiopharmaceuticals for medical imaging. Significantly, we have stream lined the production of a small carbon-11 labelled molecule - [11C]carbon disulfide - the enables the synthesis of a wide array of labelled compounds that were previously inaccessible thus opening up the possibilities to produce new and novel radio tracer molecules for PET imaging.
Exploitation Route Other groups have used this method, most recently a group in Japan have used this method to generate a carbon-11 disulfram molecule to conduct an imaging study with.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description As part of this project we have prepared a short animated clip on PET imaging. The cost of this was covered by impact funding from this grant, with the aim of communicating our research to a lay audience and also to act as an educational resource. This video has been uploaded onto YouTube and has featured on our main Imperial College website. It was first uploaded in January 2016 and has received almost 300,000 views. A link can be found here: https://www.youtube.com/watch?v=yrTy03O0gWw
First Year Of Impact 2016
Sector Education
 
Title New production method for 11CS2 
Description In the course of this research we have developed a new production route the C-11 radio labelled synthon C-11 carbon disulfide. We both refined and optimised this production method, characterising this small radio labelled molecule and further demonstrating its reactivity and applicability for the synthesis of PET tracer like molecules. The main innovation in this route was the high temperature reaction of elemental sulfur and C-11 methyl iodide which enabled the high speed and high yield reaction to produce C-11 carbon disulfide. We believe the method is now refined enough and technically viable to be implemented by others at PET centres with available C-11 equipment and infrastructure - and will thus enable a much wider use of C-11 chemistry for PET imaging. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Within a short time, this method has now gone beyond explorative and speculative radiochemistry to a method that can be used to radiolabel biological molecules that could be applied to imaging. In terms of impact, we have published further work that demonstrates this route for labelling molecules for breast cancer imaging. Further more, a least one other international radiochemistry group has used (and verified) our method and has published work in this area. 
 
Description Invicro (formerly Imanova) 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution The project ideas and intellectual/innovative aspects coming from our team.
Collaborator Contribution Project partner provided key access to radioisotopes, radiolabelling infrastructure and analytical methods.
Impact - I still continue to collaborate with this partner and have access to facilities - we have published three research papers together - this multidisciplinary with input from chemists and biologists
Start Year 2014
 
Description Prof Michael Jensen 
Organisation Technical University of Denmark
Country Denmark 
Sector Academic/University 
PI Contribution intellectual input of experiment design.
Collaborator Contribution access to specialist cyclotron and radioisotope facilities.
Impact no outputs have resulted yet
Start Year 2015