**4. Cell proliferation**

Tumor specific radiolabeled drugs are now clinically approved for non-surgical treatment and molecular imaging of malignant growth of cells and definite modifications were implemented to make possible radionuclide therapy of cancerous cells. Uptake, delivery and retaining mechanisms of radiolabeled drugs in targeted tissues and organs involve many ways which are of particular importance [60]. Normally, cells and tissues maintain a consistency between cell proliferation and cell death. On the other side, carcinogenic cells promote cell growth. In addition, amplified mitotic rate, increased cell growth and reduced differentiation are responsible for enhanced cell propagation. Generally, progression rate of cancerous cells depends upon the differentiation levels of benign and malignant tissues that leads to advanced mitotic rates [61] (**Figure 16**).

The idea of localization of radiolabeled drugs at tumor sites is best described in terms of transformed physiology of specific proliferating cells. Such localization should take place in correlation with diseased parts of the body including external and internal regions of infected areas [63]. Tumor targeting involves a certain type of interaction between medication and its receptors at affected tissue site. Malignant tumors required excess quantity of nutrition and release certain receptors which, in contrast, used as carriers to distribute cytotoxic agents as shown in the above figure. Larger number of rapidly producing cells were compared with normal cells during cell cycle i.e. S-phase. Consequently, substrate requirement in the form of nucleotides for DNA synthesis was also increased. This nucleotide incorporation into DNA of tumor cells is determined using thymidine to measure the number of proliferated cells. 11C-labeled thymidine has been utilized as PET radiotracer to image head and neck. Furthermore,

**109**

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

the desired organ.

therapeutic response.

thyroid tumors.

[66] (**Figure 17**).

in normal and cancerous cells [68].

targeted drug delivery systems necessitated drug localization and carriers within

Meanwhile, in 1972, 11C-labeled thymidine was evolved in molecular imaging to approximate cell growth. Nonetheless, rapid metabolic rate of this radiolabeled

for molecular imaging techniques to investigate cell proliferation as it provides prolonged time interval so that there will be less quantity of labeled metabolites and scanning tissues will be cleared off catabolic waste. Transportation of FLT takes place into cell through distinct transporters and enzymatic action of thymidine kinase 1 (TK1) phosphorylated radioactive tracer into 18F-FLT monophosphate that got trapped into cell. Moreover, PET images demonstrate additional phosphorylation into FLT-TP by enzyme thymidylate kinase. Reaction end products are then metabolically stuck within cells due to membrane impermeability and resistant to mortification. FLT has greater potential to evaluate the status of malignant cells for therapeutic purposes. Diverse range of melanoma tissues i.e. breast, lung, head, neck, lymphoma and gastrointestinal have been analyzed by means of fluorine labeled thymidine [65]. Finally, 18F-FLT is under evaluation and measurement of anticancer

**18F- 3′-deoxy-3′-fluorothymidine (FLT)** is significantly developed radiotracer

**18F-florouridine** as a nucleoside analogue illustrates localization by cell proliferation but the radiopharmaceutical also incorporated into DNA and RNA of tumor tissues. **11C-thymidine** was considered to observe multiplying tumor cells but prompted catabolic rates create hindrance in drug uptake volume and leads to complex imaging due to interfering catabolites (radiolabeled). **18F-1-(2′-fluoro-2′-deoxy-β-D-ribofuranosyl) thymine (FMAU**), a fluorine labeled analog of advanced stability with favorable results in animal cells. Phosphorylated complex incorporated into DNA to examine cell proliferation. Radioiodine I-131 & I-123 labeled **metaiodobenzylguanidine (MIBG)** represent the potent radioactive drug with diagnostic and therapeutic response to treat metastatic tumor. Even though, peptide receptors are now interchanging radiotherapy of neuroendocrine tumors, but the labeled drug still used to treat chromaffin tumors. Following 11C-labeled amino acid analogs, **11C-L-methionine and 11C-5-hydroxytryptophane,** are used to visualize breakdown rates of cancer cells and imaging of different phases of

An analog of dihydroxyphenylalanine, **18F-DOPA,** stored in brain tumor cells and exhibit amino acid transportation.18F-labeled synthetic amino acids i.e. L-leucine derivatives, **18F-fluoro-cyclobutyl carboxylic acid (FACBC)**, are preferentially firm and rigid with extended time frame of uptake by prostate tumor

**18F-fluoroethyl tyrosine (FET)** localized in brain tumor cells and help to determine the type of therapeutic treatment and fate of proliferating tissues. 11C and 18F labeled pyrimidine analog, **2'-Fluoro-methyl-D-arabino-furanosyluracil (FMAU)** considered worthwhile for examining multiplying tumor cells. FMAU stored in the cancerous cells, phosphorylated and incorporated into DNA by enzymatic action of DNA polymerase with the potential to image DNA replication

of thymidine integrated into DNA of malignant tissues by using **<sup>3</sup>**

drug makes it less convenient for repetitive imaging practice.

In diseased patients, diagnosis and evaluation of therapeutic response is accomplished with positron emission tomography (PET). Studies based on this technology seek imaging mediators with eminent tumor selectivity and specificity for distinct attributes [64]. In 1950s, procedures were considered to estimate quantity

**H-Thymidine**.

**Figure 16.** *Difference of cell surface receptors in normal and tumor cells [62].*

*Medical Isotopes*

**3.6 Oxidative metabolism (tissue hypoxia)**

and prospensity for metastasis [46].

advanced mitotic rates [61] (**Figure 16**).

*Difference of cell surface receptors in normal and tumor cells [62].*

**4. Cell proliferation**

Hyoxia, a phathophysiological condition portray deprived of adequate oxygen

level in tissues. A normoxic cell have oxygen level 20–80 mmHg compared to hypoxic cell <3 mmHg. In malignancies, irregular vascularization cause ischemic hypoxia. The severity of cancerous hypoxia depend upon tumor phenotype for example cervical cancer has severe hypoxic injury. Hypoxia may alter the function in tumor microenvironment particularly angiogenesis, vasculogenisis, apoptosis

Potential hypoxia selective PET radiotracer has been developed to evaluate tumor microenviroment.18F-fluoromisonidazole (FMISO) and 64Cu-[4-*N*-methyl-3-

Tumor specific radiolabeled drugs are now clinically approved for non-surgical treatment and molecular imaging of malignant growth of cells and definite modifications were implemented to make possible radionuclide therapy of cancerous cells. Uptake, delivery and retaining mechanisms of radiolabeled drugs in targeted tissues and organs involve many ways which are of particular importance [60]. Normally, cells and tissues maintain a consistency between cell proliferation and cell death. On the other side, carcinogenic cells promote cell growth. In addition, amplified mitotic rate, increased cell growth and reduced differentiation are responsible for enhanced cell propagation. Generally, progression rate of cancerous cells depends upon the differentiation levels of benign and malignant tissues that leads to

The idea of localization of radiolabeled drugs at tumor sites is best described in terms of transformed physiology of specific proliferating cells. Such localization should take place in correlation with diseased parts of the body including external and internal regions of infected areas [63]. Tumor targeting involves a certain type of interaction between medication and its receptors at affected tissue site. Malignant tumors required excess quantity of nutrition and release certain receptors which, in contrast, used as carriers to distribute cytotoxic agents as shown in the above figure. Larger number of rapidly producing cells were compared with normal cells during cell cycle i.e. S-phase. Consequently, substrate requirement in the form of nucleotides for DNA synthesis was also increased. This nucleotide incorporation into DNA of tumor cells is determined using thymidine to measure the number of proliferated cells. 11C-labeled thymidine has been utilized as PET radiotracer to image head and neck. Furthermore,

thiosemicarbazonato ligand] (ATSM) translated for hypoxia imaging [59].

**108**

**Figure 16.**

targeted drug delivery systems necessitated drug localization and carriers within the desired organ.

In diseased patients, diagnosis and evaluation of therapeutic response is accomplished with positron emission tomography (PET). Studies based on this technology seek imaging mediators with eminent tumor selectivity and specificity for distinct attributes [64]. In 1950s, procedures were considered to estimate quantity of thymidine integrated into DNA of malignant tissues by using **<sup>3</sup> H-Thymidine**. Meanwhile, in 1972, 11C-labeled thymidine was evolved in molecular imaging to approximate cell growth. Nonetheless, rapid metabolic rate of this radiolabeled drug makes it less convenient for repetitive imaging practice.

**18F- 3′-deoxy-3′-fluorothymidine (FLT)** is significantly developed radiotracer for molecular imaging techniques to investigate cell proliferation as it provides prolonged time interval so that there will be less quantity of labeled metabolites and scanning tissues will be cleared off catabolic waste. Transportation of FLT takes place into cell through distinct transporters and enzymatic action of thymidine kinase 1 (TK1) phosphorylated radioactive tracer into 18F-FLT monophosphate that got trapped into cell. Moreover, PET images demonstrate additional phosphorylation into FLT-TP by enzyme thymidylate kinase. Reaction end products are then metabolically stuck within cells due to membrane impermeability and resistant to mortification.

FLT has greater potential to evaluate the status of malignant cells for therapeutic purposes. Diverse range of melanoma tissues i.e. breast, lung, head, neck, lymphoma and gastrointestinal have been analyzed by means of fluorine labeled thymidine [65]. Finally, 18F-FLT is under evaluation and measurement of anticancer therapeutic response.

**18F-florouridine** as a nucleoside analogue illustrates localization by cell proliferation but the radiopharmaceutical also incorporated into DNA and RNA of tumor tissues. **11C-thymidine** was considered to observe multiplying tumor cells but prompted catabolic rates create hindrance in drug uptake volume and leads to complex imaging due to interfering catabolites (radiolabeled). **18F-1-(2′-fluoro-2′-deoxy-β-D-ribofuranosyl) thymine (FMAU**), a fluorine labeled analog of advanced stability with favorable results in animal cells. Phosphorylated complex incorporated into DNA to examine cell proliferation. Radioiodine I-131 & I-123 labeled **metaiodobenzylguanidine (MIBG)** represent the potent radioactive drug with diagnostic and therapeutic response to treat metastatic tumor. Even though, peptide receptors are now interchanging radiotherapy of neuroendocrine tumors, but the labeled drug still used to treat chromaffin tumors. Following 11C-labeled amino acid analogs, **11C-L-methionine and 11C-5-hydroxytryptophane,** are used to visualize breakdown rates of cancer cells and imaging of different phases of thyroid tumors.

An analog of dihydroxyphenylalanine, **18F-DOPA,** stored in brain tumor cells and exhibit amino acid transportation.18F-labeled synthetic amino acids i.e. L-leucine derivatives, **18F-fluoro-cyclobutyl carboxylic acid (FACBC)**, are preferentially firm and rigid with extended time frame of uptake by prostate tumor [66] (**Figure 17**).

**18F-fluoroethyl tyrosine (FET)** localized in brain tumor cells and help to determine the type of therapeutic treatment and fate of proliferating tissues. 11C and 18F labeled pyrimidine analog, **2'-Fluoro-methyl-D-arabino-furanosyluracil (FMAU)** considered worthwhile for examining multiplying tumor cells. FMAU stored in the cancerous cells, phosphorylated and incorporated into DNA by enzymatic action of DNA polymerase with the potential to image DNA replication in normal and cancerous cells [68].

**Figure 17.** *Pathophysiological mechanisms of significant radiotracers used in investigation of malignant cells [67].*
