**3.2 Iron metabolism**

For the development of new radiopharmaceuticals similarities with ferric ion (Fe+3) was very important as iron is a fundamental part of our body and many iron binding proteins likewise transferrin, lactoferrin and ferritin transport and store iron in-vivo. 67Ga++ ion produced at physiological pH its infection uptake is multifactorial since it shares similar chemical characteristic and biodistribution properties with ferric ion (Fe+3). When 67Ga- citrate administrated in blood plasma due to the increase cell permeability and blood flow about 90% activity exchange ligand

#### **Figure 14.**

*Reduction reaction of 2-Deoxy-2-[18F] fluoro-D-glucose to 2-Deoxy-2-[18F] fluoro-D-sorbitol using NaBH4 reducing agent.*

with plasma protein in extracellular space. Therefore, iron atom always competes with radio-metal (67Ga) for binding with plasma protein. 67Ga-citrate exchange ligand with transferrin protein in cell plasma. Cancerous cells overexpress cell proliferation and metabolic activities, to meet the cell membrane receptors demand tumor and inflammatory cell membranes have ubiquitous membrane receptors on them. In fact, infinite transferrin receptors are getting to the cell having rapid cell growth and upregulated DNA synthesis (like tumor and inflammatory cells), thus ensuring more uptake of 67Ga++.

67Ga-citrate localize non-specifically at the site of infection where the 67Ga-transferrin complex formed due to the leakage of plasma protein from blood vessel to extracellular space of inflamed tissues. The acidic environment of inflammatory interstitial tissue space has more lactoferrin another plasma protein secreted by stimulated or dead neutrophils, which subsequently tie with 67Ga due to higher ionic attraction [2]. Another 67Ga uptake mechanism seen in bacterial infection, a 67Ga-avid, direct attachment of 67Ga with bacterial siderophores (specific prokaryotic metal chelating peptides) [49]. Some gallium atoms also transported by circulating WBCs [40].

67Ga-citrate used primarily for the diagnosis of spondylodiskitis, moreover for benign and neoplastic lymphomas particularly in evaluating staging, prognosis and follow up imaging of residual disease. Though 67Ga-citrate not being specific for bacterial infection and replaced with 18F-FDG/PET but still 67Ga-citrate are widely used to identify the site of FUO and worthwhile in nuclear oncology (Hodgkin's and non- Hodgkin lymphoma) [2, 43, 50]. Disadvantages of 67Ga may include its short physical half-life (t1/2 = 68 min), uptake in inflammation and trauma [40].

### **3.3 Amino acid metabolism**

Amino acids and proteins are the key elements in building block of life. Amino acid actively transport and uptake greaterly in the proliferating cancerous cells which reflects the increase synthesis of protein. Methionine, an essential natural occurring amino acid customize as l-[methyl-11C] methionine and potentially used in PET oncology. Additionally tyrosine, another essential amino acid analog frequently used as radiolabelled tracer. As these tyrosine tracers not involved in protein synthesis [11C] methyl-1-tyrosine,O-(2-[18F] fluoroethyl)-L-tyrosine (FET), 1-[2-18F] flourotyrosin, 1–4-[18F] fluoro-m-tyrosin and 1-[3-18F]-a-methyltyrosine (FMT), these analogs used in evaluating brain tumors, neuroendocrine tumors, prostate and pancreatic cancer uptake [45, 51, 52].

### **3.4 Lipid metabolism**

The upregulation of glycolysis, iron and amino acid metabolism in cancerous cells also characteristically agitate the lipid production. During normal

**107**

**Figure 15.**

[

[

[

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

tumors, prostate and breast malignancies [53, 54].

FMAU and [76Br] FBAU [46, 57].

**3.5 Thymidine kinase and folic acid synthesis pathway**

*De novo fatty acid synthesis mechanism using acetate substrate [55, 56].*

conditions production of triglycerides combined with long term energy reservoir. Cancerous cells do not manage the cell energy requirement with primary source; carbohydrates. So they preferentially employed lipid metabolism to meet energy requirement by producing more essential membrane phospholipids and phosphatidylcholine [46]. As a result two essential lipid production enzymes fatty acid synthase (FAS) and choline kinase (ChoK) overexpressed in lymphomas including breast, lung, colon, ovarian, and prostate cancers. So in lipid de novo synthesis FAS catalyze the acetic acid reaction for the synthesis of phospholipid phosphotidylcholine and choline kinase responsible for phosphocholine production as shown in **Figure 15**. Fatty acid radiolabelled analogs

11C]- Acetate, [11C]-Choline, [18F]-Fluorodeshydroxycholine [18F]-Choline,

18F]-Flouoethycholine used in PET oncology imaging of brain tumors, liver

Thymidine kinase; a metabolic substrate that catalyze the conversion reaction of nucleoside subunits to nucleotide units and then use these units in the synthesis of DNA. These labeled bacterial substrate initialize for SPECT [125I]-FIAU and PET

124I]-FIAU imaging. Thymidine based PET radiotracers [11C] TdR, [18F] FLT, [18F]

Folic acid; another metabolic salvage for nucleic acid synthesis (subsequently DNA synthesis) in prokaryotes. Para aminobenzoic acid (PABA) responsible for the folic acid production in microorganism and this substrate labeled with radiotracer [18F]-PABA/PET. This radiofluronated analogues [18F]-PABA holds potential for clinical translation in bacteria and poor attraction with mammalian cells [58].

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

*Medical Isotopes*

**Figure 14.**

*reducing agent.*

ensuring more uptake of 67Ga++.

circulating WBCs [40].

**3.3 Amino acid metabolism**

**3.4 Lipid metabolism**

prostate and pancreatic cancer uptake [45, 51, 52].

trauma [40].

with plasma protein in extracellular space. Therefore, iron atom always competes with radio-metal (67Ga) for binding with plasma protein. 67Ga-citrate exchange ligand with transferrin protein in cell plasma. Cancerous cells overexpress cell proliferation and metabolic activities, to meet the cell membrane receptors demand tumor and inflammatory cell membranes have ubiquitous membrane receptors on them. In fact, infinite transferrin receptors are getting to the cell having rapid cell growth and upregulated DNA synthesis (like tumor and inflammatory cells), thus

*Reduction reaction of 2-Deoxy-2-[18F] fluoro-D-glucose to 2-Deoxy-2-[18F] fluoro-D-sorbitol using NaBH4*

67Ga-citrate localize non-specifically at the site of infection where the 67Ga-transferrin complex formed due to the leakage of plasma protein from blood vessel to extracellular space of inflamed tissues. The acidic environment of inflammatory interstitial tissue space has more lactoferrin another plasma protein secreted by stimulated or dead neutrophils, which subsequently tie with 67Ga due to higher ionic attraction [2]. Another 67Ga uptake mechanism seen in bacterial infection, a 67Ga-avid, direct attachment of 67Ga with bacterial siderophores (specific prokaryotic metal chelating peptides) [49]. Some gallium atoms also transported by

67Ga-citrate used primarily for the diagnosis of spondylodiskitis, moreover for benign and neoplastic lymphomas particularly in evaluating staging, prognosis and follow up imaging of residual disease. Though 67Ga-citrate not being specific for bacterial infection and replaced with 18F-FDG/PET but still 67Ga-citrate are widely used to identify the site of FUO and worthwhile in nuclear oncology (Hodgkin's and non- Hodgkin lymphoma) [2, 43, 50]. Disadvantages of 67Ga may include its short physical half-life (t1/2 = 68 min), uptake in inflammation and

Amino acids and proteins are the key elements in building block of life. Amino acid actively transport and uptake greaterly in the proliferating cancerous cells which reflects the increase synthesis of protein. Methionine, an essential natural occurring amino acid customize as l-[methyl-11C] methionine and potentially used in PET oncology. Additionally tyrosine, another essential amino acid analog frequently used as radiolabelled tracer. As these tyrosine tracers not involved in protein synthesis [11C] methyl-1-tyrosine,O-(2-[18F] fluoroethyl)-L-tyrosine (FET), 1-[2-18F] flourotyrosin, 1–4-[18F] fluoro-m-tyrosin and 1-[3-18F]-a-methyltyrosine (FMT), these analogs used in evaluating brain tumors, neuroendocrine tumors,

The upregulation of glycolysis, iron and amino acid metabolism in cancerous cells also characteristically agitate the lipid production. During normal

**106**

conditions production of triglycerides combined with long term energy reservoir. Cancerous cells do not manage the cell energy requirement with primary source; carbohydrates. So they preferentially employed lipid metabolism to meet energy requirement by producing more essential membrane phospholipids and phosphatidylcholine [46]. As a result two essential lipid production enzymes fatty acid synthase (FAS) and choline kinase (ChoK) overexpressed in lymphomas including breast, lung, colon, ovarian, and prostate cancers. So in lipid de novo synthesis FAS catalyze the acetic acid reaction for the synthesis of phospholipid phosphotidylcholine and choline kinase responsible for phosphocholine production as shown in **Figure 15**. Fatty acid radiolabelled analogs [ 11C]- Acetate, [11C]-Choline, [18F]-Fluorodeshydroxycholine [18F]-Choline, [ 18F]-Flouoethycholine used in PET oncology imaging of brain tumors, liver tumors, prostate and breast malignancies [53, 54].

## **3.5 Thymidine kinase and folic acid synthesis pathway**

Thymidine kinase; a metabolic substrate that catalyze the conversion reaction of nucleoside subunits to nucleotide units and then use these units in the synthesis of DNA. These labeled bacterial substrate initialize for SPECT [125I]-FIAU and PET [ 124I]-FIAU imaging. Thymidine based PET radiotracers [11C] TdR, [18F] FLT, [18F] FMAU and [76Br] FBAU [46, 57].

Folic acid; another metabolic salvage for nucleic acid synthesis (subsequently DNA synthesis) in prokaryotes. Para aminobenzoic acid (PABA) responsible for the folic acid production in microorganism and this substrate labeled with radiotracer [18F]-PABA/PET. This radiofluronated analogues [18F]-PABA holds potential for clinical translation in bacteria and poor attraction with mammalian cells [58].

**Figure 15.** *De novo fatty acid synthesis mechanism using acetate substrate [55, 56].*

## **3.6 Oxidative metabolism (tissue hypoxia)**

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 and prospensity for metastasis [46].

Potential hypoxia selective PET radiotracer has been developed to evaluate tumor microenviroment.18F-fluoromisonidazole (FMISO) and 64Cu-[4-*N*-methyl-3 thiosemicarbazonato ligand] (ATSM) translated for hypoxia imaging [59].
