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compounds, the naturally occurring 19F isotope can be used with some success, and brain levels for the antidepressants fluoxetine [87] and trifluoroperazine [88] have been measured after chronic administration. Although NMR is mostly used with humans, recently brain levels of dexfenfluramine were measured using this technique both in the rhesus monkey and humans [89] and found to give similar values to those found by gas-liquid chromatography (GLC) analysis in post-mortem samples from both species. |
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The PET technique takes this concept one step further. By external body monitoring, it measures the decay of administered radio nucleotides that have an excess of positrons such as 11C, 13N, 15O, and 18F. The emitted positively charged positrons collide with the negative electrons in the tissue and send out simultaneously, at right angles, a pair of photons. Although for normal detection approximately 50100 mC is administered, since radioactivity is annihilated with the collision and the emitted photons have such high energy (511 keV), they pass through the body safely with little tissue interaction. Externally, they can be detected by a circle of thousands of detectors. Because of the coincidence of the pair of photons, not only is this an absolute measurement of activity, similar to scintillation spectrophotometry, but also it has spatial recognition and 3 dimensional images of concentrations can be obtained. The images have less resolution (510 mm) than NMR, but when combined with the overlaid anatomical detail of NMR, these problems are minimized. The major disadvantage is the half-life of the radioisotopes, which range from 2 minutes for 15O to 20 minutes for 11C to 110 minutes for 18F, and this means that starting with the enrichment of the isotope in a cyclotron, the synthesis and purification must all take place within a short time (12 hours from start to finish). However, with rapid and efficient reactions, robotized and automatic synthetic and separation techniques, this is possible for an increasing number of compounds. Again, as with NMR, the clinical usage of this method predominates, but large machines can be used for the larger primates and increasingly, PET scanners for small animals with sufficient spatial resolution are becoming available [90,91,92] and becoming realistically cost effective [93]. |
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The SPECT technique has less spatial resolution than PET but has the advantage of, instead of imaging isotopes with ultrashort activities, using technetium-99 or iodine-123 with half-lives of 6 and 13 hours. But what is gained in this regard is lost in practice since molecules are much harder to make with these atoms compared to carbon or fluorine. However, often if a ligand is found to be useful for PET, a similar ligand with iodine attached for use with SPECT may have much wider usage. The cost of detectors may also be 5 to 10 times less than for PET, particularly for animal use [94]. |
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But what can PET or SPECT do? Table 5 provides some general uses in drug development as a whole but specifically, for kinetics, it has far-reaching possibilities by integrating not only the kinetics at the site of action, but meas- |
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