Before discussing models, it is important to consider the basic characteristics of radioactive tracers. A tracer is designed to provide information about a particular physiological function of interest, such as blood flow, blood volume, a metabolic process, a transport step, a binding process, etc. However, since any given tracer will likely have many biochemical fates following injection, great care and judgment are required to choose an appropriate compound. Ideally, the only factor controlling the uptake and distribution of the tracer will be the physiological
Figure 6.2. Overview of processes associated with delivery, uptake, binding, and clearance of a radioactive tracer X. Arterial inflow delivers X to the region of interest and venous outflow carries it away. The tracer may cross the capillary membrane and enter the tissue. From the tissue, it may be bound irreversibly or reversibly to intra- or extracellular sites, or may be metabolized (XP) into one or more chemical forms. The original labeled tracer or the metabolites may exit the tissue to the blood.
process under study. Realistically, other factors will always affect a tracer's distribution and kinetics. For example, for a receptor-binding radiotracer, regional radioactivity concentration data are affected by regional blood flow, plasma protein binding, capillary permeability, nonspecific tissue binding, receptor association and dissociation rates, free receptor concentration, tracer clearance from blood (controlled by whole-body uptake), tracer metabolism (throughout the body), and regional uptake of any radioactive metabolites. For a well-designed tracer, the net effect of these extraneous factors is minor.
A tracer may either be a direct radiolabeled version of a naturally occurring compound, an analog of a natural compound, or a unique compound, perhaps a radiolabeled drug. An analog is a compound whose chemical properties are slightly different from the natural compound to which it is related. For example, [11C]glucose is identical to glucose except for the replacement of a 12C atom with 11C. Analogs of glucose are deoxyglucose  and fluorodeoxyglucose (FDG) [2-4], which are chemically different from glucose. Often, because the naturally occurring compound has a very complex biochemical fate, a model describing the tissue radioactivity data of a directly labeled compound may need to be quite complex. A carefully designed analog can dramatically simplify the modeling and improve the sensitivity of the model to the parameter of interest. Deoxyglucose and FDG are good examples. Deoxyglucose and glucose enter cells by the same transport enzyme and are both phos-phorylated by the enzyme hexokinase. However, de-oxyglucose is not a substrate for the next enzyme in the glycolytic pathway, so deoxyglucose-6-phosphate accumulates in tissue. In this way, the tissue signal directly reflects the rate of metabolism, since there is little clearance of metabolized tracer. One important disadvantage of using an analog is that the measured kinetic parameters are those of the analog itself, not of the natural compound of interest. To correct for this, the relationship between the native compound and the radioactive analog must be determined. For deoxyglucose and FDG, this relationship is summarized by the lumped constant [1,5]. To make the analog approach widely applicable, it is necessary to test if this constant changes over a wide range of pathological conditions [5-9].
Ideally, the parameter of interest is the primary determinant of the uptake and retention of a tracer, i.e., the tissue uptake after an appropriate period is directly (i.e., linearly) proportional to this parameter. This is the case for radioactive microspheres . Many other compounds are substantially trapped in tissue shortly after uptake and are called chemical mi-crospheres [11, 12]. For this class of compounds, a single scan at an appropriate time post-injection can give sufficient information about the parameter of interest. For other tracers, which both enter and exit tissue, scanning at multiple time points post-injection may be necessary to extract useful physiological information.
It is obvious that another important attribute of a tracer is that there be sufficient uptake in the organ of interest, i.e., the radioactivity concentration must provide sufficient counting statistics in a scan of reasonable length after injection of an allowable dose. Thus, the size of the structure of interest and the characteristics of the imaging equipment can also affect the choice of an appropriate tracer.
Was this article helpful?