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Oral presentation

Positron emission tomography (PET) is a tomographic imaging technique, which allows for accurate non-invasive in vivo measurements of a whole range of regional tissue functions in man. By using different tracers, an unlimited range of physiological, biochemical and pharmacokinetic parameters can be measured. Some examples are blood flow (perfusion), blood volume (vascularity), oxygen utilisation, glucose metabolism, pre- and post-synaptic receptor density and affinity, neurotransmitter release, enzyme activity, drug delivery and uptake, gene expression, etc. This flexibility is a result of the fact that, in principle, nearly all biological molecules can be labelled with positron emitters such as carbon-11, nitrogen-13 and oxygen-15. In addition, fluorine-18 is often used as a substitute of hydrogen, which itself does not have an isotope suitable for in vivo use.

Apart from flexibility, PET is also characterised by the ability to measure regional tissue tracer concentrations with high degrees of accuracy and sensitivity. This is based on the decay characteristics of positron emitters. In tissue, the emission of a positron effectively results in the simultaneous emission of two gamma rays, each with a fixed energy of 511 keV. These two annihilation photons are emitted in opposite directions and are recorded by coincidence detection (i.e. simultaneous detection by two opposing detectors). These two detectors define the line of response along which the original annihilation took place. In other words, no lead collimators are needed, thereby providing for optimal sensitivity. As the total path length of both annihilation photons together is also known, accurate correction for tissue attenuation can be made using a separate transmission scan. Using appropriate tracer kinetic models, the measurements of tissue tracer concentrations can be translated into quantitative values of the tissue function under study.

At present, PET represents the most selective and sensitive (pico- to nano-molar range) method for measuring molecular pathways and interactions in vivo[1]. Apart from its capacity to provide new pathophysiological information on human disease, PET is also important for the objective assessment of therapeutic efficacy and plays an ever increasing role in the development of new drugs [2,3].

In those cases where it is difficult to determine whether a change is due to progression of disease or to side effects of (chronic) medication, studies can be performed in animal models of disease [4,5].

Within drug development PET can be used in three different ways. Firstly, the drug itself can be labelled and a scan with the labelled drug can be used to check uptake in the target area. This is especially important for anti-cancer drugs [6]. Although the concept is simple, practical implementation can be very difficult. It can take many years to develop the radiochemical procedure for labelling. In addition, quantification of uptake might be hampered by uptake of radioactive metabolites.

The second type of study is the measurement of functional changes, e.g. changes in perfusion or metabolism, following drug treatment. The most striking example of this type of study is the measurement of glucose metabolism as a means of monitoring response to chemotherapy [7,8].

Finally, mechanism of action can be measured directly. In particular, receptor occupancy or enzyme inhibition can be measured using establish radioligands for the molecular targets under investigation. The advantage of this approach is that it does not require radiochemical nor modelling developments. An established procedure can be used instead. In drug development this method is particularly useful in determining optimal dose and optimal dosing regimen, requiring only a limited number of normal volunteers [9,10].

References

1. T Jones: The role of positron emission tomography within the spectrum of medical imaging.

   Eur J Nucl Med 1996, 23:207-211.

2. Comar D: PET for drug development and evaluation.

   Kluwer Academic Publishers 1995.

3. WC Eckelman: Accelerating drug discovery and development through in vivo imaging.

   Nucl Med Biol 2002, 29:777-782.

4. AA Lammertsma, SP Hume, R Myers, S Ashworth, PM Bloomfield, S Rajeswaran, T Spinks, T Jones: PET scanners for small animals.

   J Nucl Med 1995, 36:2391-2392.

5. SP Hume, AA Lammertsma, R Myers, S Rajeswaran, PM Bloomfield, S Ashworth, RA Fricker, EM Torres, I Watson, T Jones: The potential of high-resolution positron emission tomography to monitor striatal dopaminergic function in rat models of disease.

   J Neurosci Methods 1996, 67:103-112. Publisher Full Text

6. Propper DJ, de Bono J, Saleem A, Ellard S, Flanagan E, Paul J, Ganesan TS, Talbot DC, Aboagye EO, Price P, Harris AL, Twelves C: Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

   . J Clin Oncol 2003, 21:203-210. Publisher Full Text

7. Anderson H, Price P, Blomley M, Leach MO, Workman P: Measuring changes in human tumour vasculature in response to therapy using functional imaging techniques.

   Br J Cancer 2001, 85:1085-1093. Publisher Full Text

8. Hoekstra CJ, Hoekstra OS, Stroobants SG, Vansteenkiste J, Nuyts J, Smit EF, Boers M, Twisk JWR, Lammertsma AA: Methods to monitor response to chemotherapy in non-small cell lung cancer with 18F-FDG PET.

   J Nucl Med 2002, 43:1304-1309.

9. Bench CJ, Lammertsma AA, Dolan RJ, Grasby PM, Warrington SJ, Gunn K, Cuddigan M, Turton DJ, Osman S, Frackowiak RSJ: Dose dependent occupancy of central dopamine D₂ receptors by the novel neuroleptic CP-88,059-01: A study using positron emission tomography and ¹¹C-raclopride.

   Psychopharmacology 1993, 112:308-314.

10. Bench CJ, Lammertsma AA, Grasby PM, Dolan RJ, Warrington SJ, Boyce M, Gunn K, Brannick LY, Frackowiak RSJ: The time course of binding to striatal dopamine D₂ receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography.

    Psychopharmacology 1996, 124:141-147.

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