*2.2.2 Mechanism of 99mTc- Sestamibi*

*Medical Isotopes*

by alveolar-capillary diffusion method.

tumor/abnormality easily, showing a + scan.

highlights the affected areas as hot-spots [7].

by urinary system.

Other examples:

−

netate (99mTcO4

of lungs. The flow is smooth until and unless discontinued due to the presence of hinderance in airways. After entering the pulmonary circulation, gases leave lungs

A chief factor that has a key role in localization mechanism of radio tracer in brain region is barrier of blood and brain (brain–blood barrier/BBB). It is basically a uniform film of endothelial cells belonging to cerebral vessels, restricting the diffusion of lipophobic molecules, and allowing only lipophilic ones. Due to some physiological abnormalities, this barrier is interrupted allowing the diffusion of hydrophilic molecules in tissues of brain. Oxygen, electrolytes, CO, glucose, water and other smaller molecules diffuses passively in across barrier and use active mechanism to move in the neural cells, while immuno-globulins (large particles), many lipophobic radiotracers and other lipophobic (hydrophilic) particles cannot cross the barrier under normal circumstances but in situations when barrier is disrupted the radiotracers accumulate at the area of

A typical radiopharmaceutical for brain imaging by 99mTc-DTPA. Normally,

10–20 millicurie of 99mTc-DTPA is injected intra-venously in the body and after an hour scanned via gamma cameras. If the scan shows no agglomeration of radiotracer in brain, it means that the barrier is intact, and the tracer was not able to past across the barrier. But if the scans show tracer concentration in the cells of brain it means the barrier is no more intact and is prevailed by anomalies. So, the tracer

Other radiotracers that are involved in such type of study (that localize passively in brain) are 99mTc-glucoheptonate (GH),123I-serum albumin, technetium pertech-

*(A) Illustration of intact barrier in the brain cells that do not allow 99mTc-DTPA to diffuse, (B) disruption of* 

) [9], Thallous chloride Tl-201 [10, 11], Gallium citrate Ga-67 [12].

it cannot diffuse across barrier easily because of its lipophobic nature (See **Figure 1(A)**), but in abnormalities like tumor and infections the barrier is disturbed, so, 99mTc-DTPA move passively across barrier and amass in the infected area of brain (See **Figure 1(B)**). Its biologic half-life is 1–2 hours, halftime for clearance of plasma is 70 minutes and in 24 hours 90% of the tracer is eliminated

*2.2.1 Mechanism of 99mTc-DTPA (diethylene triamine penta-acetic acid)*

**92**

**Figure 1.**

*barrier in the brain cells [8].*

99mTc labeled cationic, lipophilic tracers like furifosmin, tetrofosmin and Sestamibi for myocardial perfusion imaging have been established. 99mTc-Sestamibi is some-what similar to cationic 201Tl+ but Sestamibi transport across the membrane only involves passive diffusion [13]. In start, it was assumed that the uptake of technetium labeled Sestamibi by the myocardial cells is primarily because of binding of lipid constituents to the membrane of cell. This ambiguity was later cleared that uptake was not because of membrane's binding to lipid constituent, instead the cellular entry is chiefly linked to mitochondria and its negative potential of inner membrane. About 90% of uptake was linked to mitochondria [14] (See **Figure 2(A)**). It was studied that the upholding of technetium labeled Sestamibi is not specific to tumor of some organs, rather it is a general mechanism.

99mTc- Sestamibi moves passively from blood to tumor and amass in the cancers that have low multidrug-resistant pump expression and more mitochondria making cancers susceptible to precise diagnosis. But in most cases, the resistance pump dominates over mitochondrial presence making cancers non-susceptible to 99mTc-Sestamibi, because the resistance pumps eject the radiotracer out of the cell [15]. So, the upholding status of this radiotracer reflects the membrane permeability of mitochondria and the mitochondrial potentials. Alterations due to cancers leads to dys-functioning of mitochondria that consequently cause decreased uptake of tracer [16] (See **Figure 2(B)**). The decreased upholding of technetium Sestamibi in the terms of chemotherapy (after chemotherapeutic session) is correlated to the over-expression of multidrug-resistant proteins. So, the cancers which do not uphold this tracer are not prone to chemotherapy.

#### **Figure 2.**

*(A) Normal binding of 99mTc- Sestamibi to mitochondria, (B) over-expression of resistance pump that quickly removes 99mTc-sestamibi out of cell, (C) effect of Bcl-2, an anti-apoptotic protein; that halts the binding of 99mTc-sestamibi to mitochondria [17].*

#### *Medical Isotopes*

The other possibility is that the protein that prevents the induction of apoptosis (Bcl-2, prevents the membrane permeability of mitochondria) maybe over expressed, halting the entry of radiotracers in mitochondria [18] (See **Figure 2(C)**).

Few compounds to suppress/neutralize the effects of anti-apoptotic protein have been subjected to clinical trials. The purpose for this is to monitor the credibility and efficacy of ongoing therapeutic procedure.

#### **2.3 Phagocytosis**

The word "Phagocytosis" derived from Greek language that translate as "CELL EATING" (a procedure in which cell engulfs a particle and internalizes it). A prime example involves Kupffer cells (that present in the lining of liver and involve in the breakdown of red blood cells also known as phagocytic cells) in the reticuloendothelial system entrapped the radio-labeled colloidal particles following an intravenous injection [19]. The particle size of radiolabeled colloidal suspensions is usually between 0.05 to 4 μm. 99mTc-macro-aggregated albumin and 99mTc-sulfur colloid are mostly used as phagocytic agents and their size ranging from approximately 0.1–2.0 μm are able to leave the circulation via the sinusoidal type capillary structures in the liver, spleen, and bone marrow [20]. There is inverse relation between particle size and its bone marrow uptake that is why the larger particles will localize in spleen and liver.

The diameter of capillary is about seven micro-meters which is larger than particle size, capillary blockade does not occur. Opsonin (serum specific protein) may interrelate and provide coating to the colloids so that may be recognize by receptors site; then, engulf and removed from circulation by cells of the reticuloendothelial system as shown in **Figure 3** [21].

Macrophages in liver sinusoids (Kupffer cells) and macrophages in spleen (reticular cells) accumulate the particles by phagocytosis. In a liver scan with 99mTc-sulfur colloid cold lesions identified may be due to intra hepatic tumor displacing normal distribution of reticuloendothelial system's cells. Similarly, decreased reticuloendothelial system functioning may appear as radiation damage in bone marrow and liver shown as cold areas in scan results. Patients having melanoma and breast cancer, 99mTc-SC has been widely used in lympho-scintigraphy for the identification of sentinel node which is the first lymph node to receive lymphatic drainage from tumor cells [22].

**95**

**Figure 4.**

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

5–10 minutes of intravenous colloidal injection [23].

capillary beds as shown in **Figure 4** [19, 25].

**2.4 Capillary blockade**

half-lives [27].

Distribution in the endothelial system is typically Five percent in marrow, Ten percent in spleen and eighty-five percent in liver. The tbiol of macro-aggregated albumin is 6–12 hours which is infinitely short as compared to tbiol of 99mTc-sulfur colloid in the liver. T ½ of clearance from the blood pool is 2.5 min; so, in approximately ten minutes only 6% remains in blood stream. Imaging must begin after

The radiopharmaceutical, Tc-99 m sulfur colloid, is localized by this mechanism used for liver scans. Cyst, tumor abscess or hemangioma are focal areas of lacking phagocytic cells will be demonstrated as "Areas of lack uptake". There will be a colloid shift if liver is poorly functioning such as with cirrhosis or hepatitis [22, 24].

This technique most precisely depends upon the phenomenon of microembolization (trapping the radiolabeled particles in the capillary bed) used to determine perfusion of organ such as brain, heart, and lung. For pulmonary perfusion studies commonly used radiolabeled particles is Technetium labeled macro aggregated albumin particles. 99mTc-MAA particles have diameter of about 10–50 μm while, pre-capillaries and capillaries have a mean diameter of 20–25 μm and 8 μm, respectively. Therefore, intravenous injection of 99mTc-MAA particles block the blood flow to the distal region of lung by physically trapped in arterio-

Smaller particles pass through the pulmonary capillaries and are extracted by the reticuloendothelial system in the body. Therefore, the mechanism of localization of particles in lungs is purely a mechanical process, called capillary blockade. In experimental animal studies, gold standard for determination of organ perfusion is radiolabeled microspheres with varying particle diameter and physical

The first encountered capillary beds are the lungs when such sized particles injected intravenously. For perfusion lung scan radiolabeled particles (Tc-99 m

*Illustration of capillary blockade due to 99mTc-MAA accumulation in capillary beds [26].*

#### **94**

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

Distribution in the endothelial system is typically Five percent in marrow, Ten percent in spleen and eighty-five percent in liver. The tbiol of macro-aggregated albumin is 6–12 hours which is infinitely short as compared to tbiol of 99mTc-sulfur colloid in the liver. T ½ of clearance from the blood pool is 2.5 min; so, in approximately ten minutes only 6% remains in blood stream. Imaging must begin after 5–10 minutes of intravenous colloidal injection [23].

The radiopharmaceutical, Tc-99 m sulfur colloid, is localized by this mechanism used for liver scans. Cyst, tumor abscess or hemangioma are focal areas of lacking phagocytic cells will be demonstrated as "Areas of lack uptake". There will be a colloid shift if liver is poorly functioning such as with cirrhosis or hepatitis [22, 24].

## **2.4 Capillary blockade**

*Medical Isotopes*

**2.3 Phagocytosis**

system as shown in **Figure 3** [21].

**94**

**Figure 3.**

*Phagocytosis process through macrophages of liver (Kupffer cells) present in the lining of liver [20].*

The other possibility is that the protein that prevents the induction of apoptosis (Bcl-2, prevents the membrane permeability of mitochondria) maybe over expressed, halting the entry of radiotracers in mitochondria [18] (See **Figure 2(C)**). Few compounds to suppress/neutralize the effects of anti-apoptotic protein have been subjected to clinical trials. The purpose for this is to monitor the credibility

The word "Phagocytosis" derived from Greek language that translate as "CELL EATING" (a procedure in which cell engulfs a particle and internalizes it). A prime example involves Kupffer cells (that present in the lining of liver and involve in the breakdown of red blood cells also known as phagocytic cells) in the reticuloendothelial system entrapped the radio-labeled colloidal particles following an intravenous injection [19]. The particle size of radiolabeled colloidal suspensions is usually between 0.05 to 4 μm. 99mTc-macro-aggregated albumin and 99mTc-sulfur colloid are mostly used as phagocytic agents and their size ranging from approximately 0.1–2.0 μm are able to leave the circulation via the sinusoidal type capillary structures in the liver, spleen, and bone marrow [20]. There is inverse relation between particle size and its bone marrow

The diameter of capillary is about seven micro-meters which is larger than particle size, capillary blockade does not occur. Opsonin (serum specific protein) may interrelate and provide coating to the colloids so that may be recognize by receptors site; then, engulf and removed from circulation by cells of the reticuloendothelial

Macrophages in liver sinusoids (Kupffer cells) and macrophages in spleen (reticular cells) accumulate the particles by phagocytosis. In a liver scan with 99mTc-sulfur colloid cold lesions identified may be due to intra hepatic tumor displacing normal distribution of reticuloendothelial system's cells. Similarly, decreased reticuloendothelial system functioning may appear as radiation damage in bone marrow and liver shown as cold areas in scan results. Patients having melanoma and breast cancer, 99mTc-SC has been widely used in lympho-scintigraphy for the identification of sentinel node which

uptake that is why the larger particles will localize in spleen and liver.

is the first lymph node to receive lymphatic drainage from tumor cells [22].

and efficacy of ongoing therapeutic procedure.

This technique most precisely depends upon the phenomenon of microembolization (trapping the radiolabeled particles in the capillary bed) used to determine perfusion of organ such as brain, heart, and lung. For pulmonary perfusion studies commonly used radiolabeled particles is Technetium labeled macro aggregated albumin particles. 99mTc-MAA particles have diameter of about 10–50 μm while, pre-capillaries and capillaries have a mean diameter of 20–25 μm and 8 μm, respectively. Therefore, intravenous injection of 99mTc-MAA particles block the blood flow to the distal region of lung by physically trapped in arteriocapillary beds as shown in **Figure 4** [19, 25].

Smaller particles pass through the pulmonary capillaries and are extracted by the reticuloendothelial system in the body. Therefore, the mechanism of localization of particles in lungs is purely a mechanical process, called capillary blockade. In experimental animal studies, gold standard for determination of organ perfusion is radiolabeled microspheres with varying particle diameter and physical half-lives [27].

The first encountered capillary beds are the lungs when such sized particles injected intravenously. For perfusion lung scan radiolabeled particles (Tc-99 m

macro-aggregated albumin) have been used. This delivery mechanism necessarily involves to the capillary beds via blood flow, localization of Tc-99 m MAA is a surrogate for relative blood flow in lungs. Therefore, this perfusion lung scan with Tc-99 m MAA aggregates also used to assess blood flow in pulmonary arteries. A similar procedure in which Tc-99 m MAA is injected in hepatic artery through a catheter, it is delivered via hepatic blood flow to the capillaries in the liver [19, 28].
