**2.10 Facilitated diffusion**

A type of carrier-mediated transport across membranes is known as facilitated diffusion. Essentially, a carrier is utilized to carry the molecule across the membrane so, it is a selective carrier membrane (i.e., only certain molecules fit into the carrier). Consequently, it is inhibited by the presence of similar molecules that also fit into the carrier. Saturation can be achieved to maximum due to limited number of carriers. Facilitated diffusion expends passive so it entails a concentration gradient for its functioning. However, external energy is not employed in facilitated diffusion.

Glucose is the key example of facilitated diffusion. Glucose move into the cells by transmembrane protein transporters [GLUT]. Similarly, radiolabeled analog of glucose F-18 fludeoxyglucose (FDG), goes into the cells via the glucose transporters [GLUT]. After entering the cell, both glucose and FDG are phosphorylated by hexokinase. Glucose-6-phosphate then enters the glycolytic pathway. But the metabolism of FDG-6-phosphate is further blocked, so FDG is reserved in the cells. It is significant to summon up that glucose and FDG are competing for GLUT transporters, consequently prominent blood levels of glucose will reduce the cellular uptake of FDG [19] (See **Figure 12**).

## **2.11 Cellular migration**

A physiological migration directed by cell especially in response to some stimuli. The principle example is taxis of WBCs in response to inflammatory chemokines and cytokines. Ex-vivo labeling of 99mTc-HMPAO and 111In-oxyquinoline with phagocytic

#### **Figure 12.**

*Glucose and FDG transported inside cell, phosphorylated by hexokinase. 18F-FDG-6-phosphate did not metabolized further but glucose-6-phosphate continue metabolism in cell mitochondria. Tumor cell, ischemic myocytes and macrophage acquired more 18F-FDG [45].*

**103**

**Figure 13.**

*Localization Mechanisms of Radiopharmaceuticals DOI: http://dx.doi.org/10.5772/intechopen.94099*

leukocytes (mainly neutrophil) are frequently used complexes for infection and sterile inflammation site studies. Physiologically, autologous leukocytes chemotactically migrate towards pathogens in fact studies extended the use of leukocytes for radiolabeling that not only invade pathogens but also diagnose infection foci. At least 2000 or more leukocyte per microliter should be labeled for better quality image [40]. Labeled leukocytes were mostly neutrophil so that these complexes more sensitive to the neutrophil mediated infections. The uptake and rate of migration of radiolabelled cells depends upon the site of infection, virulence, stage of infection,

kind of pathogen, upon antibiotic therapy and angiogenesis of tissues [41]. Ex-vivo labelling of 111In- oxyquninoline with leukocytes was initiated by McAfee and Thakur [42]. The 111In-oxine was neutral, lipid soluble, non-specific blood cells labeling agent that passively penetrate through bilayer membrane and bind with cytosol component (lactoferrin; iron bounded protein released by neutrophil). The lactoferrin bind with indium more firmly than oxine and free oxine (8-hydroxyquinoline) leave the cell environment. Scintigraphy using 111In-oxine (8-hydroxyquinoline) with labeled leukocytes (WBCs) were the clinically proved

Approximately after 1 hour of injection, about 60% radioactivity of indium labeled leukocytes were found in the lungs and if not damaged migrate to liver, spleen, bone marrow and reticuloendothelial system. In case of infection, radiolabeled WBCs accumulate at the site of infection due to chemotactic attraction of biofilms and other soluble products of bacteria. The reason for the regular usage of 111In- leukocyte for tumor imaging were its stability, normal body distribution and complementary bone marrow imaging as shown in **Figure 13**. The cons of complex are its lower sensitivity in infection that cannot elicit the neutrophil response e.g. tuberculosis and about 18 to 30 h delay in injection administration and imaging [40].

*Depiction of tumor cell microenvironment. 111In-oxine labeled with leukocytes. Leukocytes move within blood stream and act as first line of defense. Attached radiotracer (111In) image tumor cell microenvironment [45].*

agent of choice for detecting infection foci accurately [43, 44].

#### *Localization Mechanisms of Radiopharmaceuticals DOI: http://dx.doi.org/10.5772/intechopen.94099*

*Medical Isotopes*

diffusion.

**2.10 Facilitated diffusion**

of FDG [19] (See **Figure 12**).

**2.11 Cellular migration**

A second radiopharmaceutical is rubidium chloride which falls just below the potassium in periodic table has somewhat similar properties and fits in sodium/ potassium pump, thus utilizing for PET myocardial perfusion scans [39].

A type of carrier-mediated transport across membranes is known as facilitated diffusion. Essentially, a carrier is utilized to carry the molecule across the membrane so, it is a selective carrier membrane (i.e., only certain molecules fit into the carrier). Consequently, it is inhibited by the presence of similar molecules that also fit into the carrier. Saturation can be achieved to maximum due to limited number of carriers. Facilitated diffusion expends passive so it entails a concentration gradient for its functioning. However, external energy is not employed in facilitated

Glucose is the key example of facilitated diffusion. Glucose move into the cells by transmembrane protein transporters [GLUT]. Similarly, radiolabeled analog of glucose F-18 fludeoxyglucose (FDG), goes into the cells via the glucose transporters [GLUT]. After entering the cell, both glucose and FDG are phosphorylated by hexokinase. Glucose-6-phosphate then enters the glycolytic pathway. But the metabolism of FDG-6-phosphate is further blocked, so FDG is reserved in the cells. It is significant to summon up that glucose and FDG are competing for GLUT transporters, consequently prominent blood levels of glucose will reduce the cellular uptake

A physiological migration directed by cell especially in response to some stimuli. The principle example is taxis of WBCs in response to inflammatory chemokines and cytokines. Ex-vivo labeling of 99mTc-HMPAO and 111In-oxyquinoline with phagocytic

*Glucose and FDG transported inside cell, phosphorylated by hexokinase. 18F-FDG-6-phosphate did not metabolized further but glucose-6-phosphate continue metabolism in cell mitochondria. Tumor cell, ischemic* 

**102**

**Figure 12.**

*myocytes and macrophage acquired more 18F-FDG [45].*

leukocytes (mainly neutrophil) are frequently used complexes for infection and sterile inflammation site studies. Physiologically, autologous leukocytes chemotactically migrate towards pathogens in fact studies extended the use of leukocytes for radiolabeling that not only invade pathogens but also diagnose infection foci. At least 2000 or more leukocyte per microliter should be labeled for better quality image [40]. Labeled leukocytes were mostly neutrophil so that these complexes more sensitive to the neutrophil mediated infections. The uptake and rate of migration of radiolabelled cells depends upon the site of infection, virulence, stage of infection, kind of pathogen, upon antibiotic therapy and angiogenesis of tissues [41].

Ex-vivo labelling of 111In- oxyquninoline with leukocytes was initiated by McAfee and Thakur [42]. The 111In-oxine was neutral, lipid soluble, non-specific blood cells labeling agent that passively penetrate through bilayer membrane and bind with cytosol component (lactoferrin; iron bounded protein released by neutrophil). The lactoferrin bind with indium more firmly than oxine and free oxine (8-hydroxyquinoline) leave the cell environment. Scintigraphy using 111In-oxine (8-hydroxyquinoline) with labeled leukocytes (WBCs) were the clinically proved agent of choice for detecting infection foci accurately [43, 44].

Approximately after 1 hour of injection, about 60% radioactivity of indium labeled leukocytes were found in the lungs and if not damaged migrate to liver, spleen, bone marrow and reticuloendothelial system. In case of infection, radiolabeled WBCs accumulate at the site of infection due to chemotactic attraction of biofilms and other soluble products of bacteria. The reason for the regular usage of 111In- leukocyte for tumor imaging were its stability, normal body distribution and complementary bone marrow imaging as shown in **Figure 13**. The cons of complex are its lower sensitivity in infection that cannot elicit the neutrophil response e.g. tuberculosis and about 18 to 30 h delay in injection administration and imaging [40].

#### **Figure 13.**

*Depiction of tumor cell microenvironment. 111In-oxine labeled with leukocytes. Leukocytes move within blood stream and act as first line of defense. Attached radiotracer (111In) image tumor cell microenvironment [45].*

111In-oxine labeled leukocytes preferably practiced for the diagnosis and therapy of inflammatory bowel disease, osteomyelitis, abdominal infection, diabetic foot, vascular prosthesis, pelvic sepsis, lung infection, fever of unknown origin, neurological infection, and endocarditis etc. Furthermore, for the ex-vivo radio-labeling sterile conditions should be taken because there was a possible risk of cross contamination that may be tainted with hepatitis B, C or HIV.

**99mTc- exametazime (HMPAO)** labeled with autologus leukocytes (predominantly neutrophils) follow the same pathway for infection and inflammation imaging as 111In-oxine labeled leukocytes. Neutrophil, an important part of our innate immune system moved towards acute infection foci and invade pathogens [45]. Labelling of leukocytes followed by intervenously administration of radiolabelled complex, due to inflammatory cytokines and chemokines; WBCs were attracted towards infection site. The 99mTc-leukocyte detect abnormalities soon after the injection and image not only reticuloendotelial system but also visualize urinary tract, bowl and gall bladder. Limitation includes the short half life of 99mTc and delayed bone marrow imaging (2 to 3 days between leukocyte imaging and bone marrow imaging) [40].

Platelets; an important part of thrombus formation, when **labeled with 111In** can follow simple cell migration mechanism to incorporate inside active thrombus formation so that easily picturize the thrombus formation**. Heat damaged 99mTc-RBCs** taken up for the examination of splenic nodule tissue formed after splectomy. During circulation of old and new RBCs, the old and damaged one was sequenter in the spleen. In same way heat damaged labeled RBCs sequenter inside spleen and imaged accessory spleen tissues [45].
