LC-MS/MS in development and production of novel PET radiopharmaceuticals (tracers)

Over the past decades, the most important advances in biomedical research have been in the fields of molecular biology and cell biology. Critical molecular changes that take place during the development and progression of disease have been unraveled. The discovery of novel molecular targets, related to disease states, has boosted the design of cutting edge (bio)pharmaceuticals for both diagnosis and therapy. Positron emission tomography (PET) is the technique of choice for imaging molecular processes and targets at a picomolar level. PET plays a key role in rapid diagnosis of disease, efficient development of novel (targeted) drugs and therapies, and individualization of treatment by patient selection and monitoring response to therapy. The department of Nuclear Medicine & PET research (NGP) of the VU University Medical Center (VUmc) has a strong national and international reputation, being a center of excellence in PET methodology along the entire line from radionuclide production, radiochemistry, pharmacokinetic modeling to clinical PET implementation. With respect to radiochemistry, a unique national position has been obtained in the fields of tracer development and production for clinical use, with appropriate EU GMP (good manufacturing practice) production licenses being in place. In 1996, VUmc initiated the supply of 18FDG in The Netherlands, thereby boosting the application of PET in Dutch healthcare. This year there will be 35 clinical PET or PET-CT scanners in The Netherlands, as well as several experimental scanners, most of them relying on tracers produced at VUmc. Tracer development at NGP is concentrated at its Radionuclide Center. At this site both classical as well as novel (sometimes proprietary) tracers are developed and produced, ranging from radiolabeled small molecules to monoclonal antibodies. The rapid implementation of PET technology is associated with (1) increased demand for novel PET tracers, (2) more stringent pharmaceutical requirements for tracer quality as set by national and EU authorities for investigational medical products, and (3) increased demand for accurate quantification of PET images. Availability of the latest innovative LC-MS/MS mass spectrometry systems for integrated quantitative as well as qualitative analysis, whilst being validated and FDA/EMEA approved for working in a GMP compliant setting, is indispensable to fulfill these needs and to enable progress beyond the current state of the art. LC-MS/MS provides unparalleled performance for sensitive identification, characterization and quantification of small molecules, and therefore will strongly contribute to efficient tracer development, sensitive quality/purity control of tracers, and efficient and large-scale analyses of tracers and their metabolites in plasma samples. The latter is required to enable accurate quantification of PET data. Many local, national and international PET research programs will benefit from such an investment. New clinical PET tracers, analogous to 18FDG in recent years, will progressively provide a significant contribution to health care benefits (and economics), such as efficient drug development and early (and accurate) diagnosis. In addition, tailored therapy and monitoring of response will contribute to higher life expectancy and improved quality of life.