Optimised Production of Commercial Grade Fluorine-18 Medical Imaging Agents

Lead Research Organisation: Newcastle University
Department Name: School of Chemistry

Abstract

Positron Emission Tomography (PET) is a non-invasive medical imaging technique which allows the bio-distribution and pharmacokinetics of labelled molecules to be determined in vivo. Due to these key advantages over other imaging modalities (e.g. MRI, CT, X-ray) the global demand for PET imaging services has seen significant increases with 1.8 million clinical procedures ($332M) being conducted in 2007, a 21% rise on 2006. This rapid growth is expected to continue long term, as access to PET services increases generally, and particularly outside the US, with 7.1 million annual procedures predicted by 2015. However, it's highly significant to the current proposal that the vast majority (>95%) of this market currently only involves the application of a single imaging agent; [18F]FDG, which is generic, and as such typically only used to detect metabolically active tumours in oncology.This surprising lack of suitable imaging agents is the direct result of current limitations in conventional synthetic radiochemical methods, which place severe restrictions on both the positioning of a fluorine-18 label within individual imaging molecules, and the classes of molecule that can actually be effectively used as imaging agents. Indeed, in most cases multiple steps and multiple pot transformations are required to synthesise suitable tracers, but the very short half-life of fluorine-18 (half-life = 110 min) coupled to the complexity of the requisite methodology, make process automation, pre-clinical to clinical research translation, and therapeutic and/or diagnostic area expansion (e.g. neurology, endocrinology, and cardiology etc) extremely difficult.To meet this burgeoning need researchers at Newcastle University have developed the first generic, efficient, and highly selective approach to the formation of [18F]fluoroarene imaging agents. The process places little or no restriction on the substrate thereby allowing the production of multiple tracer candidates that have been previously unobtainable using traditional synthetic approaches. Moreover, the technology uses a 'one-step-one-pot' process, irrespective of the primary substrate. This is both essential with a view to future process automation and existing technology-fit , and of critical significance from the perspective of end stage GMP grade manufacture.By way of example, 4[18F]SFB is a key imaging agent widely used in pre-clinical research to label peptides and other bio-macromolecules, but to date, is yet to realise its true clinical potential as its production typically involves a laborious and complex 'three-step-three-pot' process. However, using proprietary methodology a 'one-step-one-pot' process for the production of this agent has been developed, and has also provided the only route to 2[18F]SFB and 3[18F]SFB derivatives, allowing further refinement and optimisation of these agents.In summary the technology developed at Newcastle makes possible for the first time, the highly efficient and cost effective preparation of multiple imaging agents, to be used in a diverse range of diagnostic and/or therapeutic applications. Clinical access to such a library not only brings the goals of personalised medicine that much closer, but also goes a considerable distance towards meeting the requirements of clinical, academic and industrial PET researchers globally.

Planned Impact

The provision of an extensive 'on-demand' range of imaging agents to the global healthcare community not only benefits the individual but informs directly national and international policy on population health through effective control and management of disease leading to enhanced quality of life. Short-term impact, <2 years: - academic, industrial and clinical PET researchers (through access to 'single-pot-single-step' methodology to both known and novel fluorine-18 radiopharmaceuticals). This may also be extended to other areas of radiochemistry e.g. T, 14C and the production of SPECT imaging agents. - imaging technology providers (through compatibility with existing platform technologies and the expected additional clinical applications of PET imaging) - pharmaceutical/biotech industries (through provision of in vivo PET biomarkers to facilitate early candidate selection in product pipelines) - patients in selected therapeutic areas (through more efficient production of 'known' PET imaging agents and an increase in their availability) - extension of routine PET applications beyond oncology (through making novel PET imaging agents available for the first time) - the PDRA working in highly multi-disciplinary environment (academic/commercial/healthcare) will develop a unique skills set with focus in an area of strategic importance. Long-term impact, 5-50 years: - the global patient population (through improved diagnosis and disease management using PET) - economy (through an increase in the health and well being of the global population, the installation of imaging infrastructure and the independent creation of wealth arising from an enhanced understanding of complex biological systems - biotech sector) - chemical manufacture (through the development of clean, efficient chemical technologies and associated engineering solutions) Dissemination The proposed technology will rapidly be implemented in other PET centres via the informal research networks already established with procedures made readily available to end-users (e.g. via the online 'Google Group' 'PET Chem Com' http://groups.google.com/group/pet-chem-com for all those interested in PET radiochemistry), an active conference programme (e.g. Society of Nuclear Medicine, International Isotope Society, International Symposium on Radiopharmaceuticals) also allows new connections to be established as preliminary data is reported and discussed. Given the commercial nature of the proposal, selected publication in specialist journals (e.g. Journal of Labelled, Compounds & Radiopharmaceuticals, Nuclear Medicine and Biology) is critical in gaining acceptance of the technology by the imaging community, in addition open access publication will also facilitate the wider adoption of the generic methodology e.g. Newcastle e-prints repository: http://eprints.ncl.ac.uk. In summary, the proposed work will have an immediate worldwide impact on patients and healthcare provision in the initial target therapeutic areas. Longer term this will be extended to encompass all the major diseases currently afflicting the global population with the benefits becoming increasingly widespread and impacting on all aspects of the economy. The development of hypervalent iodine chemistry and the technology essential for medical imaging applications will also have a long term influence on the implementation of sustainable chemical manufacture. Training in the multi-disciplinary imaging environment will embed this approach in research communities within both the academic and commercial sectors enhancing the interactions with other stake-holders and facilitating the identification and realisation of opportunities.

Publications

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Description EPSRC
Amount £104,088 (GBP)
Funding ID Knowledge Transfer Fellow 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
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