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

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); 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> s<sup>−</sup><sup>1</sup> (20 MHz and 37°C) (**Tables 1**–**4**).

## **2.1 Linear chelates**

*Rare Earth Elements and Their Minerals*

brain tumor [6, 7].

by GBCAs in the units of mM<sup>−</sup><sup>1</sup>

0.47 T and 37°C in plasma [9].

**1.4 Safety**

is 0.2 mmol kg<sup>−</sup><sup>1</sup>

**1.3 Relaxivity**

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

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

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

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

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.

in mice. To prevent the toxicity of Gd3+ ions, chelate ligands are

(1/T1, 2)obs = (1/T1, 2)d + r1, 2 [Gd] (1)

s<sup>−</sup><sup>1</sup>

when measured at

 s<sup>−</sup><sup>1</sup> [2].

particular, MS-325 has an r1 relaxivity as high as 28 ± 1 mM<sup>−</sup><sup>1</sup>

**50**

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


**Table 1.**

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


### **Table 2.**

*Acute intravenous toxicity in rats [14].*

### *Rare Earth Elements and Their Minerals*

