George Charles de Hevesy is usually considered the first to identify the tracer principle . In 1923, he used 212Pb (half life = 10.6 hr) to study the uptake of solutions in bean plants. Although lead is generally considered toxic, he was able to use small, non-toxic amounts because of the sensitivity of the radioactivity techniques. The following year he carried out the first experiment in animals using 210Bi to label and follow the circulation of bismuth in rabbits after intra-muscular injection of bismuth-containing antisyphilitic drugs. Martin D. Kamen, in the three editions of his book titled Isotopic Tracers in Biology, chronicled the rapid progress in applying the newly discovered tracer principle to clinical research . Even today it is the only method of monitoring low concentrations of either receptor or enzymes using external imaging.
Compared with other external imaging modalities, the radiotracer approach requires injection of the least amount of mass to obtain the necessary biochemical information. The high specific activity of the radioli-gands allows detection of very low density sites. For example, for 11C or 18F-labelled radiopharmaceuticals, the specific activity at the time of injection is usually greater than 37TBq/mM (1000 Ci/mM). Since the ra-diopharmaceutical is injected in amounts approximating 370MBq, the associated mass injected is 10 nM in a 70 kg human. This amount is minimal compared with
Magnetic Resonance Imaging (MRI), which requires concentrations of 10 to100 |M/kg (~700 to 7000 |M) for iodinated contrast media where a concentration of >100 |M (~7 mM) is required. The advantage of using smaller amounts can be seen from the Scatchard transformation of the equilibrium binding constant. At high specific activity, the bound-to-free ratio (B/F) reaches a maximum in that (Bmax - B) / KD approaches Bmax/KD where Bmax represents the free receptor concentration and KD is the dissociation equilibrium constant. At lower specific activity, the ratio is decreased, or in the extreme case the receptor will be saturated . In general, these saturating concentrations using radioli-gands will still be orders of magnitude less concentrated than those required for MRI and CT. However, the higher instrument resolution of MRI and CT is a driving force to apply these tracer principles to MRI contrast media and iodinated contrast media. An example of the effect of injected dose can be seen from data showing binding of the muscarinic M2 subtype-specific ligand FP-TZTP [(1,2,5-thiadiazol-4-yl)-tetrahydro-1-methylpyridine]. As the dose of injected material increases, the percent injected dose (%ID) decreases (Fig. 17.1). A saturating amount of drug can be estimated from such studies. In this particular example, the receptor is easily saturated at 140 | M/kg, a much lower amount than the 700 to 7000 |M/kg required for standard MRI studies.
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