Microfluidic reactors for the rapid synthesis of 11C-labelled molecules for PET imaging
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
In this project we aim to develop and exploit a new technology for the fast 11C isotopic labelling of molecules of biomedical interest. More specifically we propose to develop a microfluidic reaction system for the rapid labelling of target molecules using 11CO as a radionuclide source. In this device we propose to have: a) one component (based on transition metal complexes) for the pre-concentration of 11CO; and b) a solid-supported palladium catalyst to accelerate the reaction of this gas with specific substrates for the synthesis of labelled molecules of biomedical interest. This two-stage approach will help to overcome the 2 major drawbacks that currently hinder 11CO labelling methodologies, namely poor reactivity and low concentrations of CO. Our final aim is to have an enabling technology to perform all the steps required for PET imaging with 11C-labelled probes within 15min, including a) pre-concentration of 11CO; b) catalytic reactions to incorporate 11CO onto the target molecule; c) purify labelled species; d) use the labelled probe for PET imaging.
Publications
Buscemi G
(2011)
Rapid carbonylative coupling reactions using palladium(I) dimers: applications to 11CO-radiolabelling for the synthesis of PET tracers.
in Organic & biomolecular chemistry
Faulkner S
(2011)
Radiopharmaceuticals for imaging and therapy
in Dalton Transactions
Gong X
(2012)
Gas-liquid segmented flow microfluidics for screening Pd-catalyzed carbonylation reactions.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Miller PW
(2011)
Rapid carbon-11 radiolabelling for PET using microfluidics.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Tate C
(2012)
Reversible carbon monoxide binding at copper(I) P-S-X (X = N, O) coordination polymers
in Journal of Organometallic Chemistry
Tate CW
(2012)
Hemilabile and reversible carbon monoxide binding properties of iron(II), cobalt(II) and nickel(II) complexes containing a new tridentate P-S-N ligand.
in Dalton transactions (Cambridge, England : 2003)
| Description | The key findings in this project have been in three main areas: 1) development of microfluidic systems for catalyst screening and to perform rapid carbonylative coupling reactions; 2) development of new catalytic systems (homogeneous and solid-supported) for carbonylative coupling reactions; 3) synthesis of new metal-based compounds with the ability to 'trap' and 'release' carbon monoxide. These key findings are detailed below: a) A novel gas-liquid microfluidic reactor system has been developed to study Pd-catalyzed carbonylation reactions over a range of flow regimes and reaction conditions (Chem. Eur. J. 2012, 18, 2768). We have shown that segmented gas-liquid flow regime, in comparison to annular flow, enables reactions to be studied over longer reaction times and without the build-up of unwanted Pd particles. This system has allowed us to compare the catalytic activity (in-chip) of one of the palladium dimers described above with that of a mono-palladium complex typically used for this type of reaction. b) A gas/liquid microfluidic reactor (not based on segmented flow as above) has been developed and used for the first time to efficiently perform [11C]carbon monoxide carbonylation reactions for the preparation of 11C-radiolabelled amide molecules within a short timeframe (Chem. Eur. J. 2011, 17, 460). This has allowed us to prepare a wide range of 11C-labelled molecules for PET imaging, including some substrates that are biologically relevant. c) We have demonstrated that sterically-hindered di-palladium complexes act as excellent pre-catalysts for aminocarbonylations of aryl halides (Org. Biomol. Chem., 2011, 9, 3499). We have successfully applied these catalytic systems to carry out 11C-labelling of organic substrates. These studies have provided the proof of principle for the use of these dimeric species as efficient catalysts for positron emission tomography (PET) labelling. d) We have developed a catalytic system based on palladium-xantphos supported on silica for carbonylative coupling reactions (unpublished results). This material was then packed into Teflon tubing and flow catalytic reactions were carried out. Although we still need to improve on the yields of the reaction at short reaction times (to make it useful as a system for 11C-PET labelling) we have demonstrated that this system is catalytically active and superior to other solid-supported palladium materials. As part of our efforts to yield heterogeneous catalyst, we have developed another materials based on palladium nanoparticles imbedded in a silica matrix (unpublished results). e) Several new metal-based compounds have been developed to efficiently 'trap' and 'release' carbon monoxide in solution (Dalton Trans., 2012, 41, 83) and solid state (J. Organomet. Chem. 2012, 715, 39). In particular, two of these complexes (based on Co and Fe centres coordinated to hemilabile phosphines) have shown to bind CO in solution very efficiently and upon heating release it back in solution. The new complexes and their uptake/release mechanism have been characterised in detail. Preliminary studies on their use as [11C]CO pre-concentrating materials have been carried out and showed that these complexes could indeed be further developed for PET labelling studies. |
| Exploitation Route | The flow systems developed in this project, can be further optimized to deliver radiolabelled tracers in a clinical environment. This will require further investment and optimization in the future. |
| Sectors | Chemicals |
| Description | Bioinspired routes to 11C-radiolabelling |
| Amount | £90,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2011 |
| End | 09/2014 |
| Description | Government of the Swiss Confederation |
| Amount | £363,200 (GBP) |
| Funding ID | 200021_143638 / 1 |
| Organisation | Government of the Swiss Confederation |
| Sector | Public |
| Country | Switzerland |
| Start | 11/2012 |
| End | 09/2015 |
| Description | Medical Research Council |
| Amount | £90,000 (GBP) |
| Funding ID | G1000390-3/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2012 |
| End | 09/2015 |
| Description | Droplets & Microfluidics: Novel Tools in High-Throughput Biology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | |
| Results and Impact | Corday Morgan Medal Lecture Dublin City University - A plenary lecture describing the use of micro and nanofluidics in chemistry and biology (including PET labelling). |
| Year(s) Of Engagement Activity | 2010 |
| Description | London Talk! Life on a Small Scale |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Lecture at Hampton Boys School on the applications of microfluidics. Stimulate thinking |
| Year(s) Of Engagement Activity | 2010 |
| Description | Metal-Mediated Chemistry for 11CO PET Radiolabelling |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Research talk providing an overview of some of the key findings realted to palladium-catalysed reactions for PET labelling. 'Metals in Medicine' One-Day Meeting - Cardiff University |
| Year(s) Of Engagement Activity | 2011 |
| Description | Microfluidic Approaches to High-Throughput Chemistry and Biology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | |
| Results and Impact | Corday Morgan Medal Lecture University of Hull - A plenary lecture describing the use of micro and nanofluidics in chemistry and biology (including PET labelling). |
| Year(s) Of Engagement Activity | 2010 |
| Description | Molecular Imaging - PET and MRI |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Two lectures for a general chemical audience in Nanyang Technical University (Singapore) describing the principles of molecular imaging and then providing an overview of our research in this are (including 1 h lecture on our work on PET labelling). |
| Year(s) Of Engagement Activity | 2010 |
| Description | Rapid amino-carbonylation reactions using palladium(I) dimer [Pd2(u,u-X)2(PtBu3)2] precatalysts |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Type Of Presentation | paper presentation |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk on our work was presented at the International Symposia on Advancing the Chemical Sciences - Challenges in Inorganic and Materials Chemistry (ISACS 3) in Hong Kong. Potential collaborations |
| Year(s) Of Engagement Activity | 2010 |
| Description | The Incredible Shrinking Laboratory: Microfluidics and Nanochemistry |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Primary Audience | Public/other audiences |
| Results and Impact | Lecture for the general public delivered at the Richmond Scientific Society. |
| Year(s) Of Engagement Activity | 2012 |