The blood-brain barrier (BBB) plays an important role in the mechanism of localization of many radiopharmaceuticals in the brain. The endothelial cells of the cerebral vessels form a continuous layer without gap junctions, preventing diffusion of water-soluble molecules.

In certain pathological conditions, the BBB is disrupted, allowing water-soluble molecules to diffuse from the blood into brain tissue.

Brain perfusion-imaging agents such as ^99mTc-HMPAO and ^99mTc-ECD are lipophilic radiotracers that cross the BBB via passive diffusion. The extraction of these tracers by the brain tissue is proportional to regional cerebral blood flow (rCBF). The retention of these tracers within the neuronal tissue following diffusion and extraction is assumed to be due to intracellular binding or metabolic degradation to polar metabolites or charged complexes that cannot be washed out of the cell by back diffusion as exemplified by the cellular retention of ^99mTc-ECD and ^99mTc-pertechnetate in labeled RBC. With ^99mTC-ECD the radiotracer freely diffuses into the brain tissue, where it is hydrolyzed by the action of esterase to an acid which is trapped in the brain tissue. For ^99mTcO4, the tracer is reduced intracellulary by the circulating stannous ion, and the reduced ^99mTc binds to Hgb to form ^99mTcHgb that does not diffuse out of the brain tissue.

A number of ^99mTc radiopharmaceuticals such as sestamibi and tetrofosmin have been developed for imaging myocardial perfusion. Although ^99mTc-sestamibi is cationic, similar to ²⁰¹Tl+, the transport of this agent through the cell membrane involves only passive diffusion [2].

The myocardial cell uptake of ^99mTc-sestamibi is due to intracellular binding of ^99mTc-sestamibi associated mainly with the mitochondria. Mitochondrial retention of ^99mTc-sestamibi, however, is not organ or tumor specific, but appears to be a mechanism common to most types of tissue. The intracellular levels of Ca2+ in normal cells are significantly low. However, with irreversible ischemia, extracellular calcium enters the cell and is sequestered in the mitochondria, resulting in mitochondrial destruction. The increased calcium concentration in the mitochondria blocks ^99mTc-sestamibi binding to the mitochondria.

These ^99mTc lipophilic cationic complexes are also used for imaging of parathyroid localization, and tumor imaging and the mechanism of uptake again are associated with the mitochondria.

There are significant differences between sestamibi and tetrofosmin regarding intracellular localization based on in vitro studies. While 90 % of total sestamibi was associated with mitochondria, most of the tetrofosmin accumulated in the cytosolic fraction [3].

The transport of the tracer out of the tumor cell is mediated by P-glycoprotein (Pgp), a 17-kd plasma membrane lipoprotein encoded by the human multidrug resistance (MDR) gene, and accordingly ^99mTc sestamibi is useful for imaging Pgp expression.

This mechanism is illustrated with ⁶⁷Ga-citrate localization in a variety of tumors and inflammatory lesions. Following intravenous administration of carrier-free ⁶⁷Ga as gallium citrate, ⁶⁷Ga is bound to the iron transport glycoprotein, transferrin in normal plasma, and is transported to normal tissues and tumor sites predominantly as ⁶⁷Ga-transferrin complex [4]. The initial entry of ⁶⁷Ga into tumor tissue involves simple diffusion of the unbound or loosely bound form of ⁶⁷Ga, whereas its uptake by normal soft tissues is strongly promoted by its binding to transferrin [5]. There is increased transferrin concentration within the interstitial fluid of the tumors. The increased permeability of the tumor cell membrane compared with normal cells also accounts for increased diffusion of non-transferrin-bound gallium species into cells. The accumulation of ⁶⁷Ga within tumor cells is very much dependent upon the intracellular binding of ⁶⁷Ga to iron-binding proteins such as lactoferrin and ferritin or other higher-molecular-weight molecules which can chelate gallium with greater affinity, thereby preventing back diffusion of free gallium [6]. ⁶⁸Ga-citrate is similar to ⁶⁷Ga-citrate but is a positron-emitting radiopharmaceutical and shares the same uptake pathway. ⁶⁸Ga is produced by a ⁶⁸Ge/⁶⁸Ga generator (t _½ 68 min, β⁺ 88 %) and is not dependent on a cyclotron.

All cells use glucose to generate metabolic energy. For brain tissue, glucose is the primary source of energy, but in the heart glucose becomes the primary source of energy for ischemic myocardium. Glucose is transported into the cell across the plasma membrane by facilitated diffusion, mediated by members of the glucose transporter (Glut) protein family (Glut1–6) [7]. Similar to glucose, FDG is also transported into normal and malignant cells by facilitated diffusion.

Evaluation of hepatocyte function using radiopharmaceuticals that are excreted via biliary secretion is another example of a carrier-mediated transport mechanism. Following intravenous administration, ^99mTc-disofenin (Hepatolite) and ^99mTc-mebrofenin (Choletec) diffuse through pores in the endothelial lining of the sinusoids and bind to the anionic membrane-bound carriers on the hepatocyte. The hepatic uptake is facilitated by carrier-mediated, non-sodium-dependent, organic anionic pathways similar to that of bilirubin.

Subsequent biliary excretion of the radiotracer is relatively passive following the flow of bile through the biliary tree. The bile may be stored and concentrated temporarily in the gallbladder or excreted directly into the intestine. Since bilirubin is excreted by the same hepatocyte transport system, higher serum bilirubin levels may have a significant effect on the biodistribution and hepatic excretion of radiopharmaceuticals.

Thyroid tissue selectively traps certain anions, such as I–, TcO4–, and ClO4–, by an active transport mechanism using the same pathway; hence, they are the competitive inhibitors of each other. The clinical implication is that iodinated contrast agents or iodine-containing medications may interfere with the accumulation of ^99mTcO4 in the thyroid, thereby leading to poor image quality.

However, only iodide is used by the thyroid gland to synthesize thyroid hormones, while the other anions diffuse out of the gland. In addition to thyroid tissue, the salivary glands, stomach, bowel, and genitourinary tract show significant uptake (secretion) of radioiodide and pertechnetate.

Since the thallous ion (Tl (OH) 2+) acts as an analog of the K + ion, ²⁰¹Tl has been used to image myocardial perfusion in order to evaluate the extent of myocardial ischemia and/or infarction. Positron emitter ⁸²Rb—a monocation, like potassium—is also used for imaging myocardial perfusion. The myocardial uptake of thallium and rubidium involves active cation transport mechanisms including both passive diffusion and ATP or energy-dependent pathways [8].