with researchers at the NIH and the University of Pennsylvania around 1975. Since the human brain uses glucose as its primary energy source, the availability of the tracer led to groundbreaking studies of the human brain in health and disease. This effort was driven by the successful use of 14C-labeled deoxyglucose at the NIH by Louis Sokolov in the 1960s. Since 14C is not detectable from outside of the body, the effort went into developing a labeled analog that could be shipped from a cyclotron facility (BNL in this case) and the PET camera (the University of Pennsylvania). Thus 18F with its nearly 2-hour half-life became the radionuclide of choice.

Many more tracers are used to investigate the various neuronal systems, probing both the presynaptic and postsynaptic pathways. Several hundred tracers have been prepared and tested for their utility in investigating various enzymatic and receptor systems although only a handful are routinely used. There are tracers specifically designed to monitor cell proliferation, the hypoxic nature of cells, and cell apoptosis.

The heart of the PET camera is the detection system, which builds on scintillator detector systems developed by nuclear scientists. The vast majority of modern PET scanners make use of segmented inorganic scintillation crystals coupled to multiple photomultiplier tubes (PMT). The ideal crystal will have a high stopping power for the 511-keV annihilation photons (high photoelectric absorption), a high light output with wavelength matched to the PMT, and a fast decay time for the light, and it will be physically robust. For nearly two decades the detector material of choice was bismuth orthogermanate, a scintillator often used in basic nuclear science research. More recently, lutetium orthosilicate was introduced. Owing to its higher light output, the segmentation of the crystals could be finer, thus reducing the crystal element size from approximately (4 mm × 4 mm) to (2 mm × 2 mm). There are proposals to reduce the crystal elements to below 1 mm2. In order to accomplish such a task, the packing fraction of the crystals must be improved—in other words, the empty space between crystal elements must remain a small fraction of the total area.

The typical crystal is segmented into an 8 × 8 grid (or more) coupled to four PMTs. There is an algorithm to identify the location of the event by comparing the light sharing among the PMTs. While this scheme reduces the cost of the scanner, there is a loss in resolution owing to the approximate nature of the light-sharing approach. There are prototype scanners using avalanche photodiodes coupled to individual crystal elements, making the finer pixel identification better. Thus far such systems have been built only for small animal scanners.

As the physical limitations of detection are approached, the remaining avenue is to increase the signal to noise ratio by utilizing tracers that are uniquely suited to imaging the function in question and that otherwise clear rapidly from surrounding tissue. To this end, the development of more specific tracers is believed to be the most critical issue for PET.

One of the main strengths of PET compared to single-photon emission computed tomography (SPECT) is the ability to measure, directly, the attenuation effect of the object being viewed. This is the result of requiring that both photons be detected. Thus, if one photon of the pair is not observed, then there is no line of response. Along the path to the detectors, one or both photons (511 keV each, the rest mass of the electron) can undergo absorption. Thus, in order to be detected as an event, both photons must be detected in temporal coincidence. By using an external source of positron emitter, the attenuating (absorbing) extent of the object to be measured can be determined. All commercial PET cameras are now built with a CT scanner (X-ray tomography) so that a merged image of structure and function can be obtained. Since the CT image is a measure of electron density, it is used to calculate the necessary coefficients for attenuation correction. The primary function of the CT image is to provide a detailed view of the section of the body under investigation. Figure PET 2 illustrates the power of this approach.

There are several physical limitations inherent in PET technology. First, as the emitted positron has kinetic energy, varying from a few hundred keV to several MeV depending on



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