**1.2 Contrast mechanism**

CAs in the field of MRI alter the longitudinal (T1) and transverse (T2) relaxation rates of the surrounding water protons, therefore enhancing the image

contrast in tissue of interest [4]. MRI CAs generally behave as positive CAs on T1-weighted image (T1WI) or negative CAs on T2WI based on their relaxation mechanisms. Gadolinium-based contrast agents (GBCAs) are commonly used as T1 contrast agents that have the ability to decrease T1 relaxation times of protons and work as a positive image contrast on T1WI. GBCAs have been commercially introduced since 1988 and have been globally used for more than 25 years in more than 100 million patients, and over 10 million contrast-enhanced MRI scans were annually performed [5]. These agents distribute into plasma, interstitial spaces, and extracellular spaces immediately after intravenous injection. Since most GBCAs are employed as extracellular agents, dynamic study of MRI has been performed to detect hypervascular tumors, such as hepatocellular carcinoma. The extracellular distribution of GBCAs is most effective in detection and diagnosis of disrupted blood-brain barrier in the central nervous system such as multiple sclerosis and brain tumor [6, 7].

## **1.3 Relaxivity**

The relaxation of solvent nuclei around paramagnetic center has been described by Solomon, Bloembergen, and others [8]. Every material has proper T1 and T2 relaxation rates (1/T1, 1/T2) of water protons, and the difference of relaxivities produces the contrasts among tissues. The use of BCAs can increase both T1 and T2 relaxation rates (1/T1, 1/T2) of water protons. The observed water proton relaxation rates contribute to the contrast of the relaxation rates (1/T1, 1/T2) without GBCAs, and the increased relaxation rates (1/T1, 1/T2) are promoted using GBCAs. The increased relaxation rates of water protons are linearly related to the concentration of GBCAs within the range of clinically relevant concentrations. The relaxivity is defined as a concentration-dependent increase in relaxation rate of water protons by GBCAs in the units of mM<sup>−</sup><sup>1</sup> s<sup>−</sup><sup>1</sup> [2].

$$\text{(1/T1,2)obs} = \text{(1/T1,2)d} + \text{r1,2 [Gd]} \tag{1}$$

**51**

**Table 2.**

**Table 1.**

*Current Clinical Issues: Deposition of Gadolinium Chelates*

**2. Chelate types of gadolinium-based contrast agent**

The GBCAs are excreted from the kidney within hours after intravenous administration [11]. GBCAs are ultimately eliminated through the renal route with half-lives of 1–2 h and excreted intact in urine (more than 95% of the injected dose in 24 h). The dose of these small molecular GBCAs in clinical use is usually 100 times lower than their LD50. GBCAs used to be used as a contrast agent of MRI even for patients with chronic kidney disease (CKD). However, in 2006, nephrogenic systemic fibrosis (NSF) was reported by Grobner. Many papers reported that CKD might be the main factor of NSF [12, 13]. These days, GBCAs are not used for

GBCAs are categorized mainly into two groups: linear and macrocyclic GBCAs. In general, macrocyclic GBCAs are more stable than linear GBCAs due to higher thermodynamic and kinetic stability (**Tables 1**–**4**) [14, 15]. In clinical use, gadopentetate dimeglumine, Gd-DTPA (Magnevist); gadoterate, Gd-DOTA (Dotarem);

**Gadolinium-DTPA**: Gadopentetate dimeglumine, Gd-DTPA (Magnevist), is one of the linear-type chelating agents. Gd3+ ions are covered by the polydentate ligand like a claw (**Figure 1**). The toxicity of Gd-DTPA is more than tenfold lower than the toxicity of Gd3+ ion and DTPA as a ligand. Its safety profile is very well established with low incidence of adverse effects. The risk of adverse reactions is low when then

**Commercial name Chemical name Structure Chelate type** Magnevist Gadopentetate dimeglumine Gd-DTPA Linear Omniscan Gadodiamide Gd-DTPA-BMA Linear Dotarem Gadoterate meglumine Gd-DOTA Macrocyclic ProHance Gadoteridol Gd-HP-DO3A Macrocyclic Gadovist Gadobutrol Gd-DO3A-butrol Macrocyclic

**GBCAs LD50 (mmol/kg) References** Gd-DTPA 8 [16] Gd-DTPA-BMA 25 [18] Gd-DOTA 18 [17] Gd-HP-DO3A <15 [19] Gd-DO3A-butrol 25 [18]

s<sup>−</sup><sup>1</sup>

(20 MHz and

gadoteridol, Gd-HP-DO3A (ProHance); and gadodiamide, Gd-DTPA-BMA

(Omniscan) have similar r1 relaxivity in the range of 3.5–3.8 mM<sup>−</sup><sup>1</sup>

agent is administrated intravenously even up to doses of 0.03 mol/kg.

*Representative clinical gadolinium-based contrast agents (GBCAs).*

*GBCA, Gadolinium-based contrast agent; LD50, median lethal dose.*

*Acute intravenous toxicity in rats [14].*

*DOI: http://dx.doi.org/10.5772/intechopen.91260*

patients with CDK.

37°C) (**Tables 1**–**4**).

**2.1 Linear chelates**

Protein-binding GBCAs, Gd-BOPTA (MultiHance), Gd-EOB-DTPA (Eovist), and MS-325 (Ablaber), have increased relaxivity in plasma because of their noncovalent binding to albumin which slows down the molecular rotation [2, 8]. In particular, MS-325 has an r1 relaxivity as high as 28 ± 1 mM<sup>−</sup><sup>1</sup> s<sup>−</sup><sup>1</sup> when measured at 0.47 T and 37°C in plasma [9].

### **1.4 Safety**

Safety of GBCAs for clinical applications is another critical issue because of the reported harmful effects of Gd3+ in patients. Gd3+ ions are highly toxic in ionic form due to interference with calcium channel and protein-binding sites. This is because the ionic radius of Gd3+ ions is almost equal to that of Ca2+ and Gd3+ can compete with Ca2+ and cause toxic side effects for the biological system. Free Gd3+ ions accumulate in the spleen, liver, bone, and kidney, and LD50 of free Gd3+ ion is 0.2 mmol kg<sup>−</sup><sup>1</sup> in mice. To prevent the toxicity of Gd3+ ions, chelate ligands are employed to reduce free Gd3+ ions. Harmful Gd3+ ions may still be released from some type of chelates. The mechanism of release of free Gd3+ from chelated CAs has been investigated. One of the hypotheses is transmetallation with other metal ions, including Zn2+, Ca2+, and Cu2+ in the serum of human body. Another hypothesis is the protonation of the ligands at low pH. These factors would cause chelate dissociation in vivo [10]. Therefore, gadolinium chelate-based MRI CAs emerged for their good safety profiles and the stability for high thermodynamic and kinetic stability.

*Current Clinical Issues: Deposition of Gadolinium Chelates DOI: http://dx.doi.org/10.5772/intechopen.91260*

The GBCAs are excreted from the kidney within hours after intravenous administration [11]. GBCAs are ultimately eliminated through the renal route with half-lives of 1–2 h and excreted intact in urine (more than 95% of the injected dose in 24 h). The dose of these small molecular GBCAs in clinical use is usually 100 times lower than their LD50. GBCAs used to be used as a contrast agent of MRI even for patients with chronic kidney disease (CKD). However, in 2006, nephrogenic systemic fibrosis (NSF) was reported by Grobner. Many papers reported that CKD might be the main factor of NSF [12, 13]. These days, GBCAs are not used for patients with CDK.
